TNF signaling (Homo sapiens)

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1712, 20, 513, 5048, 71403, 25, 32, 42, 55...14, 663429, 304, 26, 5626, 62, 736, 13, 28, 751618, 70381139, 44, 465, 5338, 4966195, 5327, 452, 21, 24, 36, 61669, 37705853, 5915, 43cytosolTAB1 RBCK1 TNF(1-233) TNF(77-233) IKKA:IKKB:NEMO:GNB2L1RIPK1-containg TNFR1signaling complexesNSMAF K63pUb-K377-RIP1 UBC(305-380) activecaspase-8:viralCRMA/SPI-2UBC(1-76) IKBKG CYLD TAX1BP1 TRADD TNF(1-76) CRMA TNFRSF1A(22-455) RNF31 RIPK1 TRADD TRADD TNF(77-233) TNFRSF1A(22-455) TNF(1-233) TNFRSF1A(22-455) BIRC2 LUBAC:OTULINUBC(229-304) TRAF2 IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBTNF-alpha:TNFR1:TRADD:K63polyUb-RIPK1:BIRC2,3,4TAB3 UBB(1-76) TNF(77-233) TNF(77-233) TNF(1-233) TRADD XIAP RIPK1 K63pUb-K377-RIP1 K48polyUbSPPL2B CASP8(1-479) TNF(77-233) TAX1BP1 TRAF2 RIPK1 NSMAFTRAF2:TRADD:RIP1(325-671)p-S177,S181-IKBKB CRMA TNFRSF1A(22-455) K48polyUb TAB3 Caspase activationvia Death Receptorsin the presence ofligandXIAP CASP8(1-479)TRADD BIRC3 RIPK1 TNFRSF1A(22-455) FADD UL36 DENN-SV,MADDTRADD TRADD SMPD3 TRADD FADD TNF-alpha:TNFR1:TRADD:K63polyUb-RIPK1:BIRC2,3,4:TAX1BP1:TNFAIP3K63pUb-K377-RIP1 TNF(77-233) UBC(77-152) SHARPIN solubleTNF-alpha:TNFR1CASP8(1-479) TRADD TRAF2 TNF(1-233) UL36p-S418-CYLDBIRC2 SMPD2 TAB1:TAB2,TAB3:TAK1UBC(533-608) TRAF2 GNB2L1 TRAF2 IKBKB viral serpinsTAB2 MADD CASP8(217-374) BIRC3 BIRC2 RBCK1 BIRC2 SHARPIN TRADD BAG4 TNF(1-34)UBB(153-228) TNFRSF1A(22-455) IKBKG NSMAF TNF:TNFR1:TRADD:TRAF2:K63polyUb-RIP1:BIRC2/3:TAB1:TAK1:TAB2/3K63pUb-K377-RIP1 SPPL2A,SPPL2BCYLDTRADD TNF-alpha:TNFR1:DENN-SV,MADDGNB2L1 TNF-alpha:TNFR1:NSMAF:GNB2L1TNF(77-233) TNF(1-233) TRAF2 MAP3K7 RNF31 TNF(77-233) MAP3K7 BIRC3 K63pUb-K377-RIP1 RNF31 TNF(1-233) TNF(1-233) RIPK1 TRAF2 RIPK1 RBCK1 UBA52(1-76) RIPK1 IKBKB TRAF2:TRADD:RIPK1CASP8(217-374) SMPD2,3TNFRSF1A(22-455) BIRC2 ATPRIPK1(325-671) UBC(457-532) TRAF2 BIRC3 DENN-SV active caspase-8TNF-alphatrimer:TNF-R1trimerTNFalpha:TNF-R1:TRADD:K63polyUb-RIP1:BIRC2/3:IKKA:IKKB:NEMONSMAF TNF(52-76)UBC(609-684) IKBKG UBC(381-456) LUBACTNF(1-233) SHARPIN TNFAIP3 FADDTNF(1-233) trimerSMPD3 TNFRSF1A(22-455) TNF(77-233) TNFRSF1A(22-455) XIAP OTULINTNF(1-233) TNF-alpha:TNFR1:TRADD:RIP1:TRAF2:BIRC2/3TRADD GNB2L1K48polyUb-RIPK1-containing TNFR1 complexesTRADD:TRAF2:RIP1:FADD:CASP8(1-479)CASP8(385-479) TNF:TNFR1:TRADD:TRAF2:BIRC2/3:K63polyUB-RIP1:LUBACRegulated NecrosisXIAP TNF(1-233) TRAF1 CHUK TNF(77-233) CASP8(1-479):UL36TNF(77-233) BIRC3 XIAP BIRC3 SPPL2A TRADD:TRAF2:RIP1:FADDRBCK1 USP21 TNFalpha:TNFR1:TRADD:TRAF2:TRAF1:RIPK1OTUD7B TNFRSF1A(22-455) TNFRSF1A(22-455) TNF(1-76) trimerCHUK GNB2L1CYLD:CLIP3:TNF:TNFR1:TRADD:K63pUb-RIP1:TRAF2:BIRC2/3TRAF2 CLIP3 IKBKG TAB1 ADAM17 RIPK1RIPK1(1-324)TNF-alpha:TNFR1:NSMAF:GNB2L1:SMPD2,3TNFRSF1A(22-455) OTULIN GNB2L1 TNFRSF1A(22-455) TNF(77-233) XIAP TNFRSF1A(22-455) RNF31 TRAF2BIRC2 TNF(1-233) TNFAIP3 TNF-alpha trimer,soluble formDENN-SV BIRC2 TNF(1-233) UBC(153-228) UBB(77-152) TNF(77-233) TRAF1CYLD TRADD CRMA TNFRSF1A(22-455) TAB2 p-S176,S180-CHUK BIRC2 K63pUb-K377-RIP1 SHARPIN SMPD2 RIPK1(325-671) TNFRSF1A(22-455) BIRC3 XIAP TRADDTNF(77-233) TNF(1-233) CHUK:IKBKB:IKBKGTNF(1-233) TRAF2 TRAF2 TNFRSF1A(22-455) TNF-alpha:TNFR1:NSMAFBIRC2 TNF(1-233) CHUK TRAF2 TNF(77-233) TRAF2 TNF-alpha:TNFR1ADPSPI-2 BIRC3 RIPK1deubiquitinasesTNF(1-233) BIRC2,3,4SPI-2 USP4 TNFAIP3 TNFRSF1A:BAG4TNF(1-233) ADAM17TNF(1-233) TRAF1 TNFRSF1A(22-455) CLIP3TNF(77-233) TRAF1(164-416)BIRC3 TNF(77-233) TAX1BP1:TNFAIP3UbTRAF2 CASP8(385-479) BIRC2 MADD RPS27A(1-76) TRAF1 Zn2+ XIAP USP2 viral serpinsBAG4TNFRSF1A(22-455) TNF-alpha:TNFR1:TRADD:RIPK1:TRAF2TNF(77-233) K63polyUbIKBKB SPI-2 TRADD TRADD BIRC3 TRAF2 XIAP TRAF1(1-163)XIAP 12, 20, 51507214, 6618, 705410, 33, 651, 14, 63, 6649725372571841, 47, 53688, 23, 31, 52, 645735, 7722, 694822, 69, 76407, 7419


Description

The inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) is expressed in immune and nonimmune cell types including macrophages, T cells, mast cells, granulocytes, natural killer (NK) cells, fibroblasts, neurons, keratinocytes and smooth muscle cells as a response to tissue injury or upon immune responses to pathogenic stimuli (Köck A. et al. 1990; Dubravec DB et al. 1990; Walsh LJ et al. 1991; te Velde AA et al. 1990; Imaizumi T et al. 2000). TNF-alpha interacts with two receptors, namely TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Activation of TNFR1 can trigger multiple signal transduction pathways inducing inflammation, proliferation, survival or cell death (Ward C et al. 1999; Micheau O and Tschopp J 2003; Widera D et al. 2006). Whether a TNF-alpha-stimulated cell will survive or die is dependent on autocrine/paracrine signals, and on the cellular context.

TNF binding to TNFR1 results initially in the formation of Complex I that consists of TNFR1, TRADD (TNFR1-associated death domain), TRAF2 (TNF receptor associated factor-2), RIPK1 (receptor interacting protein kinase 1), and BIRC1 and BIRC3 (cIAP1/2,cellular inhibitor of apoptosis) (Micheau O and Tschopp J 2003). This complex by default activates NFkappaB promoting cell survival (induction of anti-apoptotic proteins such as BIRC, cFLIP) and secretion of pro-inflammatory cytokines (TNF and IL-6). When the survival pathway is inhibited, TNF-induced signaling leads to the formation of Complex II that is made up of TRADD, FADD (Fas-associated death domain-containing protein, RIPK1,and procaspase-8 leading to the activation of caspase-8 and apoptotic cell death. When caspase activity is inhibited under certain pathophysiological conditions (e.g. caspase-8 inhibitory proteins such as CrmA and vICA after infection with cowpox virus or CMV) or by pharmacological agents, deubiquitinated RIPK1 is physically and functionally engaged by its homolog RIPK3 leading to formation of the necrosome, a necroptosis-inducing complex consisting of RIPK1 and RIPK3 (Tewari M & Dixit VM 1995; Fliss PM & Brune W 2012; Sawai H 2013; Moquin DM et al. 2013; Kalai M et al. 2002; Cho YS et al. 2009, He S et al. 2009, Zhang DW et al., 2009).TNF-alpha can also activate sphingomyelinase (SMASE, such as SMPD2,3) proteins to catalyze hydrolysis of sphingomyeline into ceramide (Adam D et al.1996; Adam-Klages S et al. 1998; Ségui B et al. 2001). Activation of neutral SMPD2,3 leads to an accumulation of ceramide at the cell surface and has proinflammatory effects. However, TNF can also activate the pro-apoptotic acidic SMASE via caspase-8 mediated activation of caspase-7 which in turn proteolytically cleaves and activates the 72kDa pro-A-SMase form (Edelmann B et al. 2011). Ceramide induces anti-proliferative and pro-apoptotic responses. Further, ceramide can be converted by ceramidase into sphingosine, which in turn is phosphorylated by sphingosine kinase into sphingosine-1-phosphate (S1P). S1P exerts the opposite biological effects to ceramide by activating cytoprotective signaling to promote cell growth counteracting the apoptotic stimuli (Cuvillier O et al. 1996). Thus, TNF-alpha-induced TNFR1 activation leads to divergent intracellular signaling networks with extensive cross-talk between the pro-apoptotic pathway, and the other NFkappaB, and JNK pathways providing highly specific cell responses initiated by various types of stimuli. View original pathway at:Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 75893
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Gillespie, Marc E

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Bibliography

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History

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CompareRevisionActionTimeUserComment
101505view11:37, 1 November 2018ReactomeTeamreactome version 66
101041view21:18, 31 October 2018ReactomeTeamreactome version 65
100572view19:51, 31 October 2018ReactomeTeamreactome version 64
100121view16:36, 31 October 2018ReactomeTeamreactome version 63
99671view15:07, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99267view12:45, 31 October 2018ReactomeTeamreactome version 62
93796view13:36, 16 August 2017ReactomeTeamreactome version 61
93333view11:20, 9 August 2017ReactomeTeamreactome version 61
88403view11:38, 5 August 2016FehrhartOntology Term : 'tumor necrosis factor mediated signaling pathway' added !
87132view18:49, 18 July 2016EgonwOntology Term : 'signaling pathway' added !
86420view09:17, 11 July 2016ReactomeTeamreactome version 56
83184view10:18, 18 November 2015ReactomeTeamVersion54
81554view13:05, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADAM17 ProteinP78536 (Uniprot-TrEMBL)
ADAM17ComplexR-HSA-1251963 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
BAG4 ProteinO95429 (Uniprot-TrEMBL)
BAG4ProteinO95429 (Uniprot-TrEMBL)
BIRC2 ProteinQ13490 (Uniprot-TrEMBL)
BIRC2,3,4ComplexR-HSA-5357900 (Reactome)
BIRC3 ProteinQ13489 (Uniprot-TrEMBL)
CASP8(1-479) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(1-479):UL36ComplexR-HSA-5692539 (Reactome)
CASP8(1-479)ProteinQ14790 (Uniprot-TrEMBL)
CASP8(217-374) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(385-479) ProteinQ14790 (Uniprot-TrEMBL)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CHUK:IKBKB:IKBKGComplexR-HSA-168113 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
CLIP3 ProteinQ96DZ5 (Uniprot-TrEMBL)
CLIP3ProteinQ96DZ5 (Uniprot-TrEMBL)
CRMA ProteinP07385 (Uniprot-TrEMBL)
CYLD ProteinQ9NQC7 (Uniprot-TrEMBL)
CYLD:CLIP3:TNF:TNFR1:TRADD:K63pUb-RIP1:TRAF2:BIRC2/3ComplexR-HSA-5357950 (Reactome)
CYLDProteinQ9NQC7 (Uniprot-TrEMBL)
Caspase activation

via Death Receptors in the presence of

ligand
PathwayR-HSA-140534 (Reactome) Caspase-8 is synthesized as zymogen (procaspase-8) and is formed from procaspase-8 as a cleavage product. However, the cleavage itself appears not to be sufficient for the formation of an active caspase-8. Only the coordinated dimerization and cleavage of the zymogen produce efficient activation in vitro and apoptosis in cellular systems [Boatright KM and Salvesen GS 2003; Keller N et al 2010; Oberst A et al 2010].

The caspase-8 zymogens are present in the cells as inactive monomers, which are recruited to the death-inducing signaling complex (DISC) by homophilic interactions with the DED domain of FADD. The monomeric zymogens undergo dimerization and the subsequent conformational changes at the receptor complex, which results in the formation of catalytically active form of procaspase-8.[Boatright KM et al 2003; Donepudi M et al 2003; Keller N et al 2010; Oberst A et al 2010].

DENN-SV ProteinQ8WXG6-5 (Uniprot-TrEMBL)
DENN-SV,MADDComplexR-HSA-5626957 (Reactome)
FADD ProteinQ13158 (Uniprot-TrEMBL)
FADDProteinQ13158 (Uniprot-TrEMBL)
GNB2L1 ProteinP63244 (Uniprot-TrEMBL)
GNB2L1ProteinP63244 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBComplexR-HSA-177663 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
IKKA:IKKB:NEMO:GNB2L1ComplexR-HSA-5626968 (Reactome)
K48polyUb R-HSA-912740 (Reactome)
K48polyUb-RIPK1-containing TNFR1 complexesComplexR-HSA-5693113 (Reactome)
K48polyUbR-HSA-912740 (Reactome)
K63pUb-K377-RIP1 ProteinQ13546 (Uniprot-TrEMBL)
K63polyUbR-HSA-450152 (Reactome)
LUBAC:OTULINComplexR-HSA-5661506 (Reactome)
LUBACComplexR-HSA-5357865 (Reactome)
MADD ProteinQ8WXG6-3 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
NSMAF ProteinQ92636 (Uniprot-TrEMBL)
NSMAFProteinQ92636 (Uniprot-TrEMBL)
OTUD7B ProteinQ6GQQ9 (Uniprot-TrEMBL)
OTULIN ProteinQ96BN8 (Uniprot-TrEMBL)
OTULINProteinQ96BN8 (Uniprot-TrEMBL)
RBCK1 ProteinQ9BYM8 (Uniprot-TrEMBL)
RIPK1 deubiquitinasesComplexR-HSA-5357750 (Reactome)
RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
RIPK1(1-324)ProteinQ13546 (Uniprot-TrEMBL)
RIPK1(325-671) ProteinQ13546 (Uniprot-TrEMBL)
RIPK1-containg TNFR1 signaling complexesComplexR-HSA-5693112 (Reactome)
RIPK1ProteinQ13546 (Uniprot-TrEMBL)
RNF31 ProteinQ96EP0 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
Regulated NecrosisPathwayR-HSA-5218859 (Reactome) Necrosis has traditionally been considered as a passive, unregulated cell death. However, accumulating evidence suggests that necrosis, like apoptosis, can be executed by genetically controlled and highly regulated cellular process that is morphologically characterized by a loss of cell membrane integrity, intracellular organelles and/or the entire cell swelling (oncosis) (Rello S et al. 2005; Galluzzi L et al. 2007; Berghe TV et al. 2014). The morphological hallmarks of the nectotic death have been associated with different forms of programmed cell death including (but not limited to) parthanatos, necroptosis, glutamate-induced oxytosis, ferroptosis, inflammasome-mediated necrosis etc. Each of them can be triggered under certain pathophysiological conditions. For example UV, ROS or alkylating agents may induce poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation (parthanatos), while tumor necrosis factor (TNF) or toll like receptor ligands (LPS and dsRNA) can trigger necrosome-mediated necroptosis. The initiation events, e.g., PARP1 hyperactivation, necrosome formation, activation of NADPH oxidases, in turn trigger one or several common intracellular signals such as NAD+ and ATP-depletion, enhanced Ca2+ influx, dysregulation of the redox status, increased production of reactive oxygen species (ROS) and the activity of phospholipases. These signals affect cellular organelles and membranes leading to osmotic swelling, massive energy depletion, lipid peroxidation and the loss of lysosomal membrane integrity. Regulated or programmed necrosis eventually leads to cell lysis and release of cytoplasmic content into the extracellular region that is often associated with a tissue damage resulting in an intense inflammatory response.

The Reactome module describes necroptosis as the most characterized form of regulated necrosis. The molecular mechanisms behind the other types of regulated necrosis as well as interconnectivity among them need further studies.

SHARPIN ProteinQ9H0F6 (Uniprot-TrEMBL)
SMPD2 ProteinO60906 (Uniprot-TrEMBL)
SMPD2,3ComplexR-HSA-1606272 (Reactome)
SMPD3 ProteinQ9NY59 (Uniprot-TrEMBL)
SPI-2 ProteinP15059 (Uniprot-TrEMBL)
SPPL2A ProteinQ8TCT8 (Uniprot-TrEMBL)
SPPL2A,SPPL2BComplexR-HSA-8863102 (Reactome)
SPPL2B ProteinQ8TCT7 (Uniprot-TrEMBL)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB1:TAB2,TAB3:TAK1ComplexR-HSA-450277 (Reactome)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3 ProteinQ8N5C8 (Uniprot-TrEMBL)
TAX1BP1 ProteinQ86VP1 (Uniprot-TrEMBL)
TAX1BP1:TNFAIP3ComplexR-HSA-937339 (Reactome)
TNF(1-233) ProteinP01375 (Uniprot-TrEMBL)
TNF(1-233) trimerComplexR-HSA-3371351 (Reactome)
TNF(1-34)ProteinP01375 (Uniprot-TrEMBL)
TNF(1-76) ProteinP01375 (Uniprot-TrEMBL)
TNF(1-76) trimerComplexR-HSA-8863104 (Reactome)
TNF(52-76)ProteinP01375 (Uniprot-TrEMBL)
TNF(77-233) ProteinP01375 (Uniprot-TrEMBL)
TNF-alpha

trimer:TNF-R1

trimer
ComplexR-HSA-3371401 (Reactome)
TNF-alpha trimer, soluble formComplexR-HSA-3371370 (Reactome)
TNF-alpha:TNFR1:DENN-SV,MADDComplexR-HSA-5626965 (Reactome)
TNF-alpha:TNFR1:NSMAF:GNB2L1:SMPD2,3ComplexR-HSA-5626990 (Reactome)
TNF-alpha:TNFR1:NSMAF:GNB2L1ComplexR-HSA-5626997 (Reactome)
TNF-alpha:TNFR1:NSMAFComplexR-HSA-5626996 (Reactome)
TNF-alpha:TNFR1:TRADD:K63polyUb-RIPK1:BIRC2,3,4:TAX1BP1:TNFAIP3ComplexR-HSA-5693059 (Reactome)
TNF-alpha:TNFR1:TRADD:K63polyUb-RIPK1:BIRC2,3,4ComplexR-HSA-5357756 (Reactome)
TNF-alpha:TNFR1:TRADD:RIP1:TRAF2:BIRC2/3ComplexR-HSA-5357866 (Reactome)
TNF-alpha:TNFR1:TRADD:RIPK1:TRAF2ComplexR-HSA-140946 (Reactome)
TNF-alpha:TNFR1ComplexR-HSA-74277 (Reactome)
TNF:TNFR1:TRADD:TRAF2:BIRC2/3:K63polyUB-RIP1:LUBACComplexR-HSA-5357749 (Reactome)
TNF:TNFR1:TRADD:TRAF2:K63polyUb-RIP1:BIRC2/3:TAB1:TAK1:TAB2/3ComplexR-HSA-5357837 (Reactome)
TNFAIP3 ProteinP21580 (Uniprot-TrEMBL)
TNFRSF1A(22-455) ProteinP19438 (Uniprot-TrEMBL)
TNFRSF1A:BAG4ComplexR-HSA-5634181 (Reactome)
TNFalpha:TNF-R1:TRADD:K63polyUb-RIP1:BIRC2/3:IKKA:IKKB:NEMOComplexR-HSA-5357936 (Reactome)
TNFalpha:TNFR1:TRADD:TRAF2:TRAF1:RIPK1ComplexR-HSA-5634184 (Reactome)
TRADD ProteinQ15628 (Uniprot-TrEMBL)
TRADD:TRAF2:RIP1:FADD:CASP8(1-479)ComplexR-HSA-140976 (Reactome)
TRADD:TRAF2:RIP1:FADDComplexR-HSA-140977 (Reactome)
TRADDProteinQ15628 (Uniprot-TrEMBL)
TRAF1 ProteinQ13077 (Uniprot-TrEMBL)
TRAF1(1-163)ProteinQ13077 (Uniprot-TrEMBL)
TRAF1(164-416)ProteinQ13077 (Uniprot-TrEMBL)
TRAF1ProteinQ13077 (Uniprot-TrEMBL)
TRAF2 ProteinQ12933 (Uniprot-TrEMBL)
TRAF2:TRADD:RIP1(325-671)ComplexR-HSA-5357809 (Reactome)
TRAF2:TRADD:RIPK1ComplexR-HSA-140935 (Reactome)
TRAF2ProteinQ12933 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UL36 ProteinP16767 (Uniprot-TrEMBL)
UL36ProteinP16767 (Uniprot-TrEMBL)
USP2 ProteinO75604 (Uniprot-TrEMBL)
USP21 ProteinQ9UK80 (Uniprot-TrEMBL)
USP4 ProteinQ13107 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
XIAP ProteinP98170 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
active

caspase-8:viral

CRMA/SPI-2
ComplexR-HSA-2672221 (Reactome)
active caspase-8ComplexR-HSA-2562550 (Reactome)
p-S176,S180-CHUK ProteinO15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (Uniprot-TrEMBL)
p-S418-CYLDProteinQ9NQC7 (Uniprot-TrEMBL)
soluble TNF-alpha:TNFR1ComplexR-HSA-3371397 (Reactome)
viral serpinsComplexR-NUL-2672224 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADAM17mim-catalysisR-HSA-3371385 (Reactome)
ADPArrowR-HSA-5357831 (Reactome)
ATPR-HSA-5357831 (Reactome)
BAG4ArrowR-HSA-3371353 (Reactome)
BAG4ArrowR-HSA-83660 (Reactome)
BIRC2,3,4R-HSA-5357780 (Reactome)
CASP8(1-479):UL36ArrowR-HSA-5692550 (Reactome)
CASP8(1-479):UL36TBarR-HSA-75240 (Reactome)
CASP8(1-479)R-HSA-5692550 (Reactome)
CASP8(1-479)R-HSA-75240 (Reactome)
CHUK:IKBKB:IKBKGR-HSA-5357776 (Reactome)
CHUK:IKBKB:IKBKGR-HSA-5626962 (Reactome)
CLIP3ArrowR-HSA-5357845 (Reactome)
CLIP3R-HSA-5357928 (Reactome)
CYLD:CLIP3:TNF:TNFR1:TRADD:K63pUb-RIP1:TRAF2:BIRC2/3ArrowR-HSA-5357928 (Reactome)
CYLDR-HSA-5357831 (Reactome)
CYLDR-HSA-5357928 (Reactome)
DENN-SV,MADDR-HSA-5626953 (Reactome)
FADDR-HSA-140978 (Reactome)
GNB2L1R-HSA-5626962 (Reactome)
GNB2L1R-HSA-5626982 (Reactome)
GNB2L1TBarR-HSA-5357776 (Reactome)
IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBmim-catalysisR-HSA-5357831 (Reactome)
IKKA:IKKB:NEMO:GNB2L1ArrowR-HSA-5626962 (Reactome)
K48polyUb-RIPK1-containing TNFR1 complexesArrowR-HSA-5693108 (Reactome)
K48polyUbR-HSA-5693108 (Reactome)
K63polyUbR-HSA-5357757 (Reactome)
LUBAC:OTULINArrowR-HSA-5661517 (Reactome)
LUBACR-HSA-5357904 (Reactome)
LUBACR-HSA-5661517 (Reactome)
NSMAFR-HSA-5626988 (Reactome)
OTULINR-HSA-5661517 (Reactome)
R-HSA-140978 (Reactome) Once formed in context of the TNFR1 signaling complex the TRADD:TRAF2:RIPK1 complex may dissociate from the TNF:TNFR1 platform. With the recruitment of FADD and caspase-8 to the TRADD:TRAF2:RIPK1 complex the cell is pushed along the apoptotic pathway provided that the protective FLIP protein and TRAF2-associated BIRC (cIAPs) do not inhibit caspase-8 activation by RIPK1 and RIPK3-mediated activation of the necroptotic pathway.
R-HSA-2672196 (Reactome) SPI-2/CrmA (cytokine response modifier A) is a poxvirus gene product with homology to members of the serpin (serine protease inhibitor) superfamily. Cowpox virus-derived and vaccinia virus-derived CrmA cDNAs transfected into cells inhibits apoptosis induced by Fas-ligation and activation of TNFR1 (Tewari M and Dixit VM 1995; Miura M et al, 1995; Kettle S et al. 1997). Cowpox virus-derived CrmA was shown to selectively inhibit caspases in Fas-mediated apoptosis, showing the highest affinity for interleukin-1 beta-converting enzyme (ICE) and a similarly high affinity for caspase-8, Ki = 0.95 nM (Zhou Q et al. 1997).
R-HSA-3371353 (Reactome) The soluble form of TNF-alpha is cleaved from membrane-anchored TNF-alpha and retains the ability to bind to TNF receptor 1(TNFR1) and TNFR2.

BAG4, also known as silencer of death domain (SODD), belongs to the BAG family of anti-apoptotic proteins. Mammalian BAG4 was found to associate with TNFR1 preventing receptor signaling in the absence of ligand (Jiang Y et al. 1999; Miki K and Eddy EM 2002). Furthermore, crystallographic data and biochemical analysis showed that TNFR1 forms inactive homodimers or homotrimers in the absence of TNF by the N-terminal domain, the pre ligand assembly domain (PLAD) (Chan FK et al. 2000; Wang YL et al. 2011). Upon TNF-alpha binding BAG4 is quickly released from TNFR1 and three receptor molecules form a complex with the TNF trimer. The TNF-alpha homologue ligand, lymphotoxin-alpha (LTA, also known as TNF-beta), which as homotrimer only occurs as a soluble ligand, also interacts with TNFR1. LTA binds three receptor molecules and triggers the same effects as soluble TNF-alpha (Banner DW et al. 1993; Etemadi N et al. 2013).

The TNF-alpha:TNFR1 receptor complex then transmits the signal leading to cell death or survival. However, it remains unclear whether BAG4 binds to death domain of monomeric TNFR1 to prevent receptor oligomerization or recognizes receptor trimers to facilitate ATP-dependent TNFR1 trimer disassembly (Jiang Y et al. 1999; Miki K and Eddy EM 2002). Additionally, BAG4 is known to interact with HSP70, death receptor 3, and the anti-apoptotic protein Bcl-2 (Antoku et al. 2001; Brockmann et al. 2004; Jiang et al. 1999).

BAG4-overexpressing HeLa cells showed reduced cellular sensitivity to treatment with extracellular TNFalpha and CD95 ligand (Eichholtz-Wirth H et al. 2003). In addition, increased expression level of BAG4 in tumor cells leads to resistance of TNFalpha-induced cell death and is associated with pancreatic cancer, some types of melanoma, acute lymphoblastic leukemia etc.(Ozawa et al. 2000; Tao H et ql. 2007; Reuland SN et al. 2013). The physiological relevance of BAG4 for TNFR1 signaling, however, is difficult to judge because BAG4 knockout mice have no or only a mild effect on pro-inflammatory TNF signaling and give no evidence for an inhibitory role of BAG4 in TNFR1-induced cell death (Takada H et al. 2003; Endres R et al. 2003).

R-HSA-3371385 (Reactome) TNF-alpha is initially synthesized as a 26kDa transmembrane protein (membrane TNF-alpha), which is processed by proteolytic cleavage known as ectodomain shedding (Tang P et al. 1996). TNF-alpha-converting enzyme (TACE or ADAM17) mediates the cleavage of TNF-alpha generating the soluble 17kDa form (Robertshaw HJ & Brennan FM 2005). Inhibition of TACE activity resulted in an accumulation of unprocessed TNF-alpha on the cell surface of human monocytic cells (THP1) (Tabaka HN et al. 2012). Both membrane-bound and secreted forms of TNF-alpha are biologically active and may trigger different activities due to their differential capacities to stimulate TNFR1 and TNFR2. TNFR1 is efficiently activated by soluble and membrane TNF-alpha, TNFR2 signaling, however, is preferentially stimulated by membrane TNF-alpha while the soluble form has limited activity on this receptor despite efficient binding (Grell M et al. 1995; Grell M et al. 1998).
R-HSA-5357757 (Reactome) Receptor-interacting protein 1 (RIPK1) polyubiquitination is required for the recruitment of the downstream signaling complexes such as the IkB kinase (IKK) complex in the response to TNFR1 stimulation (Ea CK et al. 2006; Blackwell K et al. 2013). RIPK1 is polyubiquitinated at Lys377 (Ea CK et al. 2006). A point mutation of RIPK1 at Lys377 (K377R) was found to abolish its polyubiquitination and prevent the recruitment and activation of IKK and the TGF-beta activated kinase 1(TAK1) complex (Ea CK et al. 2006). TNF-alpha-induced recruitment of the IKK complex to TNFR1 is completely impaired, recruitment of TAK1 is severely reduced, and recruitment of the LUBAC E3 ligase complex, is also reduced in human RIPK1-deficient Jukart T-cells (Blackwell K et al. 2013).

Several E3 ligases are involved in TNFalpha signaling to initiate an immediate and effective host response to infection or injury. Among them are anti-apoptotic regulators BIRC2 and BIRC3, also known as inhibitor of apoptosis proteins (cIAP1/2). BIRC2/3 were found to constitutively associate with TRAF2 and via TRAF2 they were recruited to the TNFR1 signaling complex (Samuel T et al. 2006; Bertrand et al, 2008; Varfolomeev E et al, 2008). BIRC2/3 can directly ubiquitinate RIPK1 within the TNFR1 receptor complex allowing it to bind to the TAB2:TAK1 complex, a process reversed by the deubiquitinase CYLD and A20 (Bertrand et al, 2008; Varfolomeev et al, 2008; Moquin DM et al. 2013; Shembade N et al. 2010; Wertz IE et al. 2004). In conjunction with the ubiquitin conjugating enzyme (E2) enzyme UbcH5a, BIRC2/3 was shown to mediate polymerization of both K63-linked and linear Met1-linked chains on RIPK1 (Varfolomeev E et al, 2008; Bertrand et al, 2008; Blackwell K et al. 2013). TRAF2 promotes BIRC-mediated linear and K63-linked ubiquitination of RIP1(Blackwell K et al. 2013). K11-linked polyubiquitination of RIPK1 may also depend on BIRC2 and BIRC3 (Dynek JN et al. 2010).

R-HSA-5357776 (Reactome) K63-polyubiquitinated RIP1 binds to IKBKG (NEMO), resulting in the recruitment of the IKK complex to the receptor complex (Ea CK et al. 2006).

In addition, the linear polyubiquitination has been implicated in the NFkB activation. The linear ubiquitin chain assembly complex (LUBAC) ligase consisting of HOIL-1L, HOIP, and SHARPIN, specifically generates linear polyubiquitin chains (Kirisako T et al. 2006; Walczak H et al. 2012). IKBKG (NEMO), a regulatory component of the IκB kinase (IKK) complex, is a substrate of LUBAC. LUBAC-mediated IKBKG ubiquitination enhances IKBKG interaction with the TNF-alpha receptor signaling complex and stabilizes this protein complex to promote activation of NFkB (Haas TL et al. 2009).

Structural analysis revealed that NPL4 zinc finger 1 (NZF1) of HOIP can simultaneously bind both leucine zipper (CoZi) domains of NEMO (IKBKG) and ubiquitin and that both interactions are involved in the TNF alpha-mediated NFkappaB activation (Fujita H et al. 2014). In addition, NEMO (IKBKG) ubiquitination required RING-between-RING (RBR) domain of HOIL-1L (Smit JJ et al. 2013)

R-HSA-5357780 (Reactome) Activation of tumor necrosis factor receptor 1 (TNFR1) stimulates the formation of complex that consists of TNFR1, TNFR-associated via death domain (TRADD), RIPK1, TNFR-associated factor 2 (TRAF2) and cellular inhibitor of apoptosis (BIRC2/3 also known as cIAP1/2). TRAF2 and BIRC (cIAP1) were found to form a complex in solution (Zheng et al. 2010), suggesting that TNFR1:TRADD:RIPK1 receptor complex recruits the TRAF2:BIRC complex. Following TNF-alpha stimulation, RIPK1 is promptly K63-ubiquitinated at Lys377 residue by E3 ubiquitin ligases, such as BIRC2/3, to allow recruitment of the TAB2:TAK1 complex, the LUBAC and the IKK complex and eventually to stimulate the canonical NFkB activation.
R-HSA-5357828 (Reactome) Receptor-interacting protein 1 (RIP1 or RIPK1) can be a part of cell death and survival signaling complexes. Whether RIP1 functions in apoptosis, necroptosis or NFkB signaling is dependent on autocrine/paracrine signals, on the cellular context and tightly regulated posttranslational modifications of RIP1 itself. Pro-survival function of RIP1 is achieved by K63-polyubiquitination which is required for recruitment of signaling molecules/complexes such as the IKK complex and the TAB2:TAK1 complex to mediate activation of NFkB signaling (Ea CK et al. 2006). CYLD-mediated deubiquitination of RIPK1 switches its pro-survival function to caspase-mediated pro-apoptotic signaling (Fujikura D et al. 2012; Moquin DM et al. 2013). Caspase-8 (CASP8) in human and rodent cells facilitates the cleavage of kinases RIPK1 and RIPK3 and prevents RIPK1/RIPK3-dependent regulated necrosis (Lin Y et al. 1999; Hopkins-Donaldson S et al. 2000). The lack of CASP8 proteolytic activity in the presence of viral (e.g. CrmA and vICA) or pharmacological caspase inhibitors results in necroptosis induction via RIPK1 and RIPK3 (Tewari M & Dixit VM 1995; Fliss PM & Brune W 2012; Hopkins-Donaldson S et al. 2000).
R-HSA-5357831 (Reactome) CYLD is a deubiquitinating enzyme (DUB) that removes K63-linked ubiquitin chains from a large number of key signaling molecules, including tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and RIPK1. CYLD knockdown in human embryonic kidney 293 cells and human cervical carcinoma HeLa cells resulted in constitutive ubiquitination of TRAF2 (Reiley W et al. 2005) At the same time stimuli-induced TRAF2 ubiquitination was associated with site-specific phosphorylation of CYLD, a molecular event that was shown to inhibit CYLD-mediated deubquitination of TRAF2 (Reiley W et al. 2005; Hutti JE et al. 2009). Phosphorylation of CYLD was detected in TNF-alpha-stimulated HEK293T and HeLa cells, in LPS-treated BJAB cells, a human B‑cell line, human B-cell line (BJAB) and in human T-cell line Jurkat after stimulation with mitogens (Reiley W et al. 2005). Phoshorylation of CYLD was found to depend on IKKgamma, since it was blocked in IKKgamma-deficient Jurkat T cells (Reiley W et al. 2005) Transfection and in vitro kinase assays reveal that both IKKalpha and IKKbeta are able to phosphorylate CYLD (Reiley W et al. 2005). The noncanonical IKK family member IKKepsilon was also reported to phosphorylate CYLD at serine 418 inhibiting CYLD deubiquitinase activity. The phosphorylation of CYLD by IKKepsilon is thought to contribute to IKKepsilon-driven cell transformation (Hutti JE et al. 2009).
R-HSA-5357845 (Reactome) K63-deubiquitination of RIP1 abolishes its ability to activate NFkB upon TNF-alpha stimulation and leads to the formation of the cytosolic caspase-8 containing complex II and subsequent apoptosis.
R-HSA-5357860 (Reactome) Polyubiquitinated RIP1 binds to TAB2 resulting in the recruitment of the TAB2:TAK1 complex. The K63-linked ubiqitination on Lys377 of RIP1 was reporeted to mediate the association of RIP with the TAB2:TAK1 complex (Li H et al. 2006)
R-HSA-5357904 (Reactome) Ubiquitinated TRAF2 and BIRC2/3 were reported to recruit an additional E3 ligase complex, the linear ubiquitin (Ub) chain assembly complex (LUBAC). LUBAC is thought to bind K63 chains on BIRC2/3 but produce Met1-linked (also known as linear) Ub chains to facilitate recruitment and Met1-linked ubiquitination of NEMO (IKBKG), the regulatory subunit of the IKK complex (Haas TL et al. 2009). LUBAC enhances NEMO interaction with the TNFR1 receptor signaling complex and thus IKK complex, stabilizes this protein complex, and promotes efficient TNF-induced activation of NFkappaB resulting in apoptosis inhibition (Haas TL et al. 2009)

LUBAC consists of the chain-assembling E3 ligase HOIP as well as HOIL-1 and SHARPIN (Kirisako T et al. 2006; Walczak H et al. 2012). Importantly, deletion of the LUBAC component SHARPIN in mice or mutation of HOIL-1 in humans, lead to hyperinflammatory phenotypes, indicating key roles of LUBAC and linear Ub chains in the response to infection and inflammation (Gerlach B et al. 2011; Ikeda F et al. 2011; Tokunaga F et al. 2011; Boisson B et al. 2012).

HOIP belongs to the RING-between-RING (RBR) family of E3 ligases and is the catalytic component of LUBAC (Spratt DE et al. 2014). RBR E3 ligase domain and a conserved C-terminal extension of HOIP are responsible for assembling Met1-linked chains (Smit JJ et al., 2012; Stieglitz B et al. 2012 and 2013). HOIP was reported to act as RING/HECT hybrids, employing RING1 to recognize ubiquitin-loaded E2 while a conserved cysteine in RING2 domain subsequently forms a thioester intermediate with the transferred or “donor� ubiquitin (Stieglitz B et al. 2013). A Ub-associated (UBA) domain mediates interactions with HOIL-1L (Yagi H et al. 2012), while N-terminal PUB domain may be involved in interaction with regulatory proteins such as OTULIN to control NFkappaB signaling (Elliott PR et al. 2014). HOIP also comprises several NPL4 zinc finger (NZF) Ub binding domains (UBDs) that target it to ubiquitinated proteins (Haas et al. 2009; Fujita H et al. 2014).

Structural analysis revealed that NZF1 of HOIP can simultaneously bind both leucine zipper (CoZi) domains of NEMO (IKBKG) and ubiquitin and that both interactions are involved in TNF alpha-mediated NFkappaB activation (Fujita H et al. 2014). In addition, NEMO (IKBKG) ubiquitination required RBR domain of HOIL-1L (Smit JJ et al. 2013).

R-HSA-5357928 (Reactome) CAP-GLY domain containing linker protein 3 (CLIP3 or CLIPR-59) is thought to function as an adaptor protein recruiting CYLD into the TNFR1 signaling to facilitate CYLD-mediated deubiquitination of RIPK1 in TNFalpha signaling (Fujikura D et al. 2012). CLIP3-assisted CYLD-mediated K63-deubiquitination of RIPK1 may promote caspase-8 activation to induce apoptosis by TNFalpha. The effects of CLIPR-59 knockdown on apoptosis induction by TNFalpha were more effective in human cervical cancer HeLa cells than in human alveolar basal epithelial A549 cells or human fibrosarcoma HT1080 cells. These findings suggest that the role of CLIPR-59 on TNF-alpha-induced and RIP1-mediated pro-apoptotic signaling is dependent on cell type and context (Fujikura D et al. 2012).
R-HSA-5626953 (Reactome) MAPK activating death domain (MADD) and DENN-SV are known to directly interact with TNFR1 cytoplasmic tail (Al-Zoubi AM et al. 2001). MADD and DENN-SV are two of at least six splice variants of IG20 gene. MADD and DENN-SV are constitutively expressed in all tissues and at much higher levels in cancer cells and tissues (Al-Zoubi AM et al. 2001; Lim KM et al. 2004). The expression of other IG20 isoforms, such as KIAA0358 and IG20-SV4, can be restricted to certain neuronal tissues (Li L et al. 2008). Regulation of expression of various splice variants can profoundly affect cancer cell survival, proliferation, or death (Efimova EV et al. 2004). Knockdown of IG20 using short hairpin RNA (shRNA) resulted in spontaneous apoptosis in HeLa (cervical cancer), PA-1 (ovarian carcinoma), WRO (follicular carcinoma) and FRO (anaplastic carcinoma) cells (Mulherkar N et al. 2006; Mulherkar N. et al. 2007; Subramanian M et al. 2009). MADD and DENN-SV have been shown to stimulate TNF-alpha and TRAIL-induced upregulation of prosurvival proteins suppressing caspase-8 activation (Kurada BR et al. 2009; Mulherkar N. et al. 2007; Subramanian M et al. 2009).
R-HSA-5626962 (Reactome) Guanine nucleotide-binding protein subunit beta-2-like 1(GNB2L1) also known as receptor of activated protein kinase C 1 (RACK1) is reported to associate with the IKK complex in a TNF-triggered manner (Yao F et al. 2014). This interaction interfered with TRAF2-mediated recruitment and the subsequent phosphorylation of IKK triggered by TNF. By modulating the interaction between TRAF2 and the IKK complex, GNB2L1 (RACK1) regulated the level of NFkB activation in response to TNF (Yao F et al. 2014).
R-HSA-5626981 (Reactome) Sphingolipid signaling is initiated by neutral sphingomyelinase (neutral SMASE), a family of agonist-activated effector enzymes.
R-HSA-5626982 (Reactome) Guanine nucleotide-binding protein subunit beta-2-like 1 (GNB2L1), which is also known as a receptor for activated protein kinase C (RACK1), interacts with NSMAF (FAN) in vitro as shown by glutathione S-transferase-based coprecipitation assays as well as coimmunoprecipitation experiments using human embryonic kidney 293 (HEK293) cells (Tcherkasowa AE et al. 2002). Confocal laser-scanning microscopy studies suggest that overexpressed NSMAF (FAN) and GNB2L1 (RACK) colocalize at the plasma membrane together with TNFR1 (Tcherkasowa AE et al. 2002). Furthemore, isolation of TNF receptors containing vesicles from TNF-stimulated Jurkat or HeLa cells by help of biotinylated TNF and MACS Streptavidin Microbeadsderived and coupled with immunoblotting assay showed that GNB2L1(RACK1) interacts with TNFR1 (Philipp S et al. 2010). The data suggest that GNB2L1(RACK1) modulates activation of neutral sphingomyelinase (N-SMASE) triggered by TNF.
R-HSA-5626988 (Reactome) TNF-alpha-induced signaling by TNFR1 promotes the activation of sphingomyelin phosphodiesterase (sphingomyelinase or SMASE) signaling pathways. SMASE is a family of an agonist-activated effector enzymes that hydrolyze phospholipids on the membrane compartments to produce ceramide, a lipid-signaling molecule.

Factor associated with neutral sphingomyelinase activation (FAN or NSMAF) is an adaptor protein that constitutively binds to the neutral SMASE activation domain (NSD) of TNFR1 (Adam-Klages S et al. 1996). NSMAF (FAN) is thought to directly link TNFR1 to the activation of neutral sphingomyelinase (N-SMASE) such as sphingomyelin phosphodiesterase 2 or 3 (SMPD2, SMPD3).

R-HSA-5634221 (Reactome) TNF-induced NFkappaB activates a group of gene products including TNF receptor associated factor (TRAF) family members and inhibitor of apoptosis proteins (BIRC or cIAP1/2). TRAFs and cIAP1/2 proteins may function cooperatively at the earliest checkpoint to suppress TNF-alpha-induced apoptosis (Rothe M et al. 1994,1995; Wang CU et al. 1998).

The TRAFs (TRAF1 to TRAF6) are a group of structurally similar adaptor proteins, in most cases with E3 ligase activity, that are involved in downstream signaling of various cell surface receptors such as TNFR1, TNFR2, CD40, TLRs and TCR (Jang HD et al. 2001; Fotin-Mleczek M et al. 2004; Su X et al. 2006). The hallmark feature of all TRAFs is a C-terminal TRAF-domain of approximately 230 amino acids, which is responsible for homo- and heterooligomerization of TRAF molecules (Rothe M et al. 1994). The differences in amino acid sequences in TRAF-domains define the range of TRAF interaction partners. Another important structural element of TRAFs, with an exception of TRAF1, is the N-terminal RING finger domain that modulates induction of NFkappaB and MAPK activities. As TRAF1 has no RING finger domain, the effects of TRAF1 on NFkB activation are rather unclear. It is believed that TRAF1 regulates TNF receptor activity through its ability to interact with TRAF2 (Rothe M et al.1995; Zheng C et al. 2010; Fotin-Mleczek M et al. 2004). Structural and biochemical studies showed that TRAF1:TRAF2 heterotrimer (1:2) binds BIRC (cIAP2) more strongly than TRAF2 homotrimers, suggesting that TRAF1 may modulate the interaction between TRAF2 and BIRC (cIAP1/2) and thus suppress TNF-alpha induced apoptosis (Zheng C et al. 2010). Noteworthy, TRAF1:TRAF2 heterotrimers and TRAF2 homotrimers also differ in their capability with certain receptors but there seems to be no difference with respect to TNFR1 recruitment (Fotin-Mleczek M et al. 2004). On the contrary, TNF-induced caspase-mediated cleavage of TRAF1 generates a C-terminal fragment with NFkB-inhibitory, pro-apoptotic activity (Leo e et al. 2001; Jang HD et al. 2001; Henkler F et al. 2003). Thus, the current data suggest that depending on its cleavage status TRAF1 may exert either cytoprotective or cytotoxic effect in death domain-containing receptor signaling pathways.

The heteromeric complex TRAF1:TRAF2 has been also implicated in the cross-talk of TNFR1 and TNFR2 (Wicovsky A et al. 2009).

R-HSA-5634228 (Reactome) During TNF-alpha or Fas ligand-induced apoptosis TRAF1 can be processed into two fragments (Imler M et al. 2000; Leo E et al. 2001). Caspases-3, -6 and most efficiently caspase-8 cleave TRAF1 in vitro (Imler M et al. 2000; Leo E et al. 2001). Cleavage of TRAF1 occurs at the Asp-163 residue. A mutant TRAF1 (Asp163Ala) was not processed by either caspase (Imler M et al. 2000). The C-terminal cleavage product of TRAF1 was found to inhibit the induction of NFkB when co-expressed with NFkB inducers (such as TNFR1, DR3, TNFR2, Fas etc.) in human embryonic kidney 293 (HEK293) cells or upon treatment with TNF (Imler M et al. 2000; Henkler F et al. 2003). Furthermore, co-transfection of VSV-tagged IKKbeta and TRAF1(truncated or wild-type) into HEK293 or Jurkat T-cells followed by anti-VSV immunoprecipitation coupled with GST-IkB alpha immunocomplex kinase assays for IKK activity revealed that the caspase-generated TRAF1-fragment, but not TRAF1 itself inhibited IKK activation (Henkler F et al. 2003).
R-HSA-5661517 (Reactome) The linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor kappaB (NFkappaB) signaling. Deubiquitinases are key regulators of Ub signaling. OTULIN (also known as FAM105B) is an OTU domain deubiquitinase with high activity and unique specificity for Met1-linked polyUb (Keusekotten K et al. 2013; Rivkin E et al. 2013). OTULIN antagonizes processes involving LUBAC, including tumor necrosis factor alpha (TNFalpha), poly(I:C), NOD2 and Wnt signaling (Fiil BK et al. 2013; Keusekotten K et al. 2013; Rivkin E et al. 2013). OTULIN interacts directly with the N-terminal PUB domain of HOIP, a component of the LUBAC complex, via a conserved PUB-interacting motif (PIM) in OTULIN (Elliott PR et al. 2014; Schaeffer V et al. 2014). Furthermore, OTULIN phosphorylation within PIM was found to prevent the LUBAC:OTULIN complex formation (Elliott PR et al. 2014).
R-HSA-5692550 (Reactome) Human cytomegalovirus (HCMV) encodes several viral cell death inhibitors that target different key regulators of the extrinsic and intrinsic apoptotic pathways. Viral inhibitor of caspase-8 activation (vICA) protein encoded by the UL36 gene suppresses the extrinsic apoptotic signaling pathway by binding to the prodomain of caspase-8 (CASP8) and preventing its activation (Skaletskaya A et al. 2001; McCormick et al, 2010; Fliss PM & Brune W 2012).
R-HSA-5693055 (Reactome) Expression of TNFAIP3 (also known as A20) is upregulated by NFkappaB activation. TNFAIP3 (A20) is believed to inhibit NFkappaB with the help of its ubiquitin-editing functions (Wertz IE et al, 2004). The N-terminal half of TNFAIP3 harbors a deubiquitinating (DUB) domain that mediates the deubiquitination of K63-polyubiquitinated substrates such as receptor interacting protein 1 (RIPK1), an essential mediator of the proximal TNFR1 signalling complex (Shembade N et al. 2010; Wertz IE et al. 2004). The carboxy-terminal domain of TNFAIP3 (A20), composed of seven C2/C2 zinc fingers, functions as a ubiquitin ligase by polyubiquitinating target proteins with K48-linked ubiquitin chains, thereby targeting them for proteasomal degradation (Wertz IE et al. 2004). TNFAIP3 zinc fingers have been also shown to support TNFAIP3's binding to different ubiquitinated molecules (Wertz IE et al. 2004; Shembade N et al. 2010; Lu TT et al. 2013).

The Reactome pathway shows that upon TNF receptor 1 (TNFR1) stimulation, the E3 ubiquitin ligases such as baculoviral IAP repeat-containing protein (BIRC2/3 or cIAP1/2) mediate polyubiquitination of RIPK1 generating K63-linked chains. TNFAIP3 removes these K63-linked polyubiquitin chains, preventing the interaction of RIPK1 with NFkappaB essential modulator (NEMO) (Wertz IE et al. 2004). Subsequently, TNFAIP3 facilitates addition of K48-linked polyubiquitin chains to RIP1, targeting it for proteasomal degradation (Wertz IE et al. 2004). In this way, TNFAIP3 restricts TNF-induced NFkappaB signaling by sequential deubiquitination and ubiquitin-mediated degradation of RIPK1.

TNFAIP3 (A20) is thought to limit NFkappaB activation, however the inhibitory mechanisms for TNFAIP3 are not fully understood and are partially contradicting. A study with knockin mice expressing DUB-inactive Tnfaip3 C103A mutant reported that the deubiquitinase (DUB) activity was dispensable for LPS- or TNF-stimulated NFkappaB signaling (De A et al 2014). In contrast to Tnfaip3 knockout mice that develop perinatal lethality, the knockin Tnfaip3 C103A mice were normal and did not have an inflammatory phenotype (De A et al 2014). These finding are in agreement with an earlier study reporting that the Tnfaip3 C103A knockin mice were grossly normal for at least 4 months and contained a normal number of lymphocytes (Lu TT et al. 2013). In addition, bone marrow-derived macrophage cells (BMDM) from the knockin mice showed normal LPS- and TNF-induced NFkappaB activation and downstream gene expression, comparable to cells from wild-type mice (De A et al 2014). The study suggests that the deubiquitinase activity of TNFAIP3 in general is not obligate for most of the regulatory functions of TNFAIP3 and alternative mechanisms might be involved in TNFAIP3-mediated NFkappaB regulation (De A et al 2014). Indeed, there is biochemical evidence for different mechanisms that may contribute to TNFAIP3 inhibitory effects on TNFR1 pro-inflammatory signaling in a cell type-dependent manner:

  • Deubiquitination of K63-linked ubiquitin chains from RIPK1 by the OTU domain and adding of K48-linked polyubiquitin chains via its forth zinc finger (ZnF4) domain (Wertz IE et al. 2004).
  • Triggering degradation of E2 enzymes such as ubiquitin conjugating enzyme Ubc13 by adding K48-linked polyubiquitin chains and disruption of interactions between E2 and E3 (BIRC2,3 or TRAF2) enzymes in the TNFR1 pathway. This event was impaired with DUB-inactive TNFAIP3 (C103A, within the OTU domain) suggesting that there might be a crosstalk with DUB-dependent mechanisms (Shembade N et al. 2010).
  • A non-catalytic blockage of TAK1-mediated IKK activation by TNFAIP3 binding to polyubiquitin chain via its seventh zinc finger (ZnF7) and forming a complex involving specific NEMO:TNFAIP3 interaction (Skaug B et al. 2011).
  • A non-catalytic inhibition of TNF- and LUBAC-induced NFkappaB signalling by binding to linear polyubiquitin chains via its ZnF7, which prevents the LUBAC:NEMO interaction (Verhelst K et al. 2012; Tokunaga F et al. 2012).
  • Attenuation of TNFR1 signaling complex formation (He KL & Ting AT 2002).

TAX1BP1 functions as an adaptor molecule for TNFAIP3 (A20) to block TNF-alpha-stimulated signaling to NFkappaB (Shembade N et al. 2007).

R-HSA-5693108 (Reactome) TNFAIP3 (A20) is ubiquitin-editing enzyme with distinct peptidase and ligase domains. The amino-terminal domain of TNFAIP3 (A20), which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family, removes K63-linked ubiquitin chains from adaptor proteins such as receptor interacting protein 1 (RIPK1) (Shembade N et al. 2010; Wertz IE et al. 2004; He KL&Ting AT 2002). The carboxy-terminal domain of TNFAIP3 (A20), composed of seven C2/C2 zinc fingers, functions as a ubiquitin ligase by polyubiquitinating target proteins with K48-linked ubiquitin chains, thereby targeting them for proteasomal degradation (Wertz IE et al. 2004). TNFAIP3 zinc fingers have been also shown to support TNFAIP3's binding to different ubiquitinated molecules (Wertz IE et al. 2004; Shembade N et al. 2010; Lu TT et al. 2013).

The Reactome pathway shows that upon TNF receptor 1 (TNFR1) stimulation, the E3 ubiquitin ligases such as baculoviral IAP repeat-containing protein (BIRC2/3 or cIAP1/2) mediate polyubiquitination of RIPK1 generating K63-linked chains. TNFAIP3 removes these K63-linked polyubiquitin chains, preventing the interaction of RIPK1 with NFkappaB essential modulator (NEMO) (Wertz IE et al. 2004). Subsequently, TNFAIP3 facilitates addition of K48-linked polyubiquitin chains to RIP1, targeting it for proteasomal degradation (Wertz IE et al. 2004). In this way, TNFAIP3 restricts TNF-induced NFkappaB signaling by sequential deubiquitination and ubiquitin-mediated degradation of RIPK1.

TNFAIP3 (A20) is thought to limit NFkappaB activation, however the inhibitory mechanisms for TNFAIP3 are not fully understood and are partially contradicting. A study with knockin mice expressing DUB-inactive Tnfaip3 C103A mutant reported that the deubiquitinase (DUB) activity was dispensable for LPS- or TNF-stimulated NFkappaB signaling (De A et al 2014). In contrast to Tnfaip3 knockout mice that develop perinatal lethality, the knockin Tnfaip3 C103A mice were normal and did not have an inflammatory phenotype (De A et al 2014). These finding are in agreement with an earlier study reporting that the Tnfaip3 C103A knockin mice were grossly normal for at least 4 months and contained a normal number of lymphocytes (Lu TT et al. 2013). In addition, bone marrow-derived macrophage cells (BMDM) from the knockin mice showed normal LPS- and TNF-induced NFkappaB activation and downstream gene expression, comparable to cells from wild-type mice (De A et al 2014). The study suggests that the deubiquitinase activity of TNFAIP3 in general is not obligate for most of the regulatory functions of TNFAIP3 and alternative mechanisms might be involved in TNFAIP3-mediated NFkappaB regulation (De A et al 2014). Indeed, there is biochemical evidence for different mechanisms that may contribute to TNFAIP3 inhibitory effects on TNFR1 pro-inflammatory signaling in a cell type-dependent manner:

  • Deubiquitination of K63-linked ubiquitin chains from RIPK1 by the OTU domain and adding of K48-linked polyubiquitin chains via its forth zinc finger (ZnF4) domain (Wertz IE et al. 2004).
  • Triggering degradation of E2 enzymes such as ubiquitin conjugating enzyme Ubc13 by adding K48-linked polyubiquitin chains and disruption of interactions between E2 and E3 (BIRC2,3 or TRAF2) enzymes in the TNFR1 pathway. This event was impaired with DUB-inactive TNFAIP3 (C103A, within the OTU domain) suggesting that there might be a crosstalk with DUB-dependent mechanisms (Shembade N et al. 2010).
  • A non-catalytic blockage of TAK1-mediated IKK activation by TNFAIP3 binding to polyubiquitin chain via its seventh zinc finger (ZnF7) and forming a complex involving specific NEMO:TNFAIP3 interaction (Skaug B et al. 2011).
  • A non-catalytic inhibition of TNF- and LUBAC-induced NFkappaB signalling by binding to linear polyubiquitin chains via its ZnF7, which prevents the LUBAC:NEMO interaction (Verhelst K et al. 2012; Tokunaga F et al. 2012).
  • Attenuation of TNFR1 signaling complex formation (He KL & Ting AT 2002).

R-HSA-75240 (Reactome) Caspase-8-precursor (pro-caspase-8) binds TRAF2:TRADD:RIP1:FADD complex (Micheau and Tschopp, 2003).
R-HSA-83582 (Reactome) Once formed in context of the TNFR1 signaling complex the TRADD:TRAF2:RIPK1 complex may dissociate from the TNF:TNFR1 platform. With the recruitment of FADD and caspase-8 to the TRADD:TRAF2:RIPK1 complex the cell is pushed along the apoptotic pathway provided that the protective FLIP protein and TRAF2-associated BIRC (cIAPs) do not inhibit caspase-8 activation by RIPK1 and RIPK3-mediated activation of the necroptotic pathway.
R-HSA-83656 (Reactome) Once the TNF-alpha:TNFR1:TRADD:RIPK1 complex has been formed there is concomitant recruitment of TRAF2, BIRC2/3 (cIAP1/2) and then of the TAB2:TAK1 and the IKK complex. TRAF2 and BIRC (cIAP1) were found to form a complex in solution (Zheng C et al. 2010), suggesting that TNFR1:TRADD:RIPK1 receptor complex recruits the TRAF2:BIRC complex as a whole. However, the expression levels of BIRCs are typically lower compared to TRAF2 suggesting that TNF-stimulated TNFR1 complex may also recruit TRAF2 alone. RIPK1 and the TRAF2:cIAP1/2 can be released from TNFR1 receptor complex in a poorly understood process associated with internalization and after that there is the formation of a so called complex II containing the adapter protein FADD, caspase-8 and RIPK1. Complex II has the potential to activate caspase-8 (Micheau O & Tschopp J 2003). The steps leading to the JUN, NF kappaB or apoptotic pathways are rife with opportunities for modulation.
R-HSA-83660 (Reactome) BAG4, also known as silencer of death domain (SODD), belongs to the BAG family of anti-apoptotic proteins. Mammalian BAG4 was found to associate with TNFR1 preventing receptor signaling in the absence of ligand (Jiang Y et al. 1999; Miki K and Eddy EM 2002). Furthermore, crystallographic data and biochemical analysis showed that TNFR1 forms inactive homodimers or homotrimers in the absence of TNF by the N-terminal domain, the pre ligand assembly domain (PLAD) (Chan FK et al. 2000; Wang YL et al. 2011). Upon TNF-alpha binding BAG4 is quickly released from TNFR1 and three receptor molecules form a complex with the TNF trimer.

The TNF-alpha:TNFR1 receptor complex then transmits the signal leading to cell death or survival. However, it remains unclear whether BAG4 binds to death domain of monomeric TNFR1 to prevent receptor oligomerization or recognizes receptor trimers to facilitate ATP-dependent TNFR1 trimer disassembly (Jiang Y et al. 1999; Miki K and Eddy EM 2002). Additionally, BAG4 is known to interact with HSP70, death receptor 3, and the anti-apoptotic protein Bcl-2 (Antoku et al. 2001; Brockmann et al. 2004; Jiang et al. 1999).

BAG4-overexpressing HeLa cells showed reduced cellular sensitivity to treatment with extracellular TNFalpha and CD95 ligand (Eichholtz-Wirth H et al. 2003). In addition, increased expression level of BAG4 in tumor cells leads to resistance of TNFalpha-induced cell death and is associated with pancreatic cancer, some types of melanoma, acute lymphoblastic leukemia etc.(Ozawa et al. 2000; Tao H et ql. 2007; Reuland SN et al. 2013). The physiological relevance of BAG4 for TNFR1 signaling, however, is difficult to judge because BAG4 knockout mice have no or only a mild effect on pro-inflammatory TNF signaling and give no evidence for an inhibitory role of BAG4 in TNFR1-induced cell death (Takada H et al. 2003; Endres R et al. 2003).

R-HSA-8863101 (Reactome) The peptide fragment that remains after soluble TNFalpha is released by sheddases like ADAM17 is futher processed by intramembrane proteolysis, releasing an intracellular domain (ICD) into the cytoplasm and C-terminal fragments into the extracellular region (Fluhrer et al. 2006). SPP/SPPL proteins are intramembrane-cleaving aspartyl proteases. SPPL2a has been located in lysosomes/late endosomes of murine embryonic fibroblasts (Behnke et al. 2011) but when overexpressed in HeLa cells is found in significant amounts at the cell surface (Behnke et al. 2011). Overexpressed SPPL2b was detected primarily at the cell surface (Friedmann et al. 2006, Behnke et al. 2011). Overexpression or RNAi-mediated knockdown of either SPPL2a or SPPL2b in cell culture models demonstrates that both proteases are able to cleave TNFalpha (Fluhrer et al. 2006, Friedmann et al. 2006). SPPL2a/b-mediated intramembrane proteolysis of TNFalpha in bone marrow-derived dendritic cells was seen to up-regulate transcription and secretion of IL-12 (Friedmann et al. 2006). Whether TNFalpha ICD fragments can translocate to the nucleus and directly activates transcription of IL-12 gene is unknown. SPLL2a and b have a number of other substrates that suggest physiological roles within the hematopoietic system and for the regulation of inflammatory responses (Voss et al. 2013).
RIPK1 deubiquitinasesArrowR-HSA-140978 (Reactome)
RIPK1 deubiquitinasesTBarR-HSA-5357776 (Reactome)
RIPK1 deubiquitinasesTBarR-HSA-5357860 (Reactome)
RIPK1 deubiquitinasesmim-catalysisR-HSA-5357845 (Reactome)
RIPK1(1-324)ArrowR-HSA-5357828 (Reactome)
RIPK1-containg TNFR1 signaling complexesR-HSA-5693108 (Reactome)
RIPK1R-HSA-5634221 (Reactome)
RIPK1R-HSA-83656 (Reactome)
SMPD2,3R-HSA-5626981 (Reactome)
SPPL2A,SPPL2Bmim-catalysisR-HSA-8863101 (Reactome)
TAB1:TAB2,TAB3:TAK1R-HSA-5357860 (Reactome)
TAX1BP1:TNFAIP3R-HSA-5693055 (Reactome)
TAX1BP1:TNFAIP3mim-catalysisR-HSA-5693108 (Reactome)
TNF(1-233) trimerR-HSA-3371385 (Reactome)
TNF(1-233) trimerR-HSA-83660 (Reactome)
TNF(1-34)ArrowR-HSA-8863101 (Reactome)
TNF(1-76) trimerArrowR-HSA-3371385 (Reactome)
TNF(1-76) trimerR-HSA-8863101 (Reactome)
TNF(52-76)ArrowR-HSA-8863101 (Reactome)
TNF-alpha

trimer:TNF-R1

trimer
ArrowR-HSA-83582 (Reactome)
TNF-alpha

trimer:TNF-R1

trimer
R-HSA-5626953 (Reactome)
TNF-alpha

trimer:TNF-R1

trimer
R-HSA-5626988 (Reactome)
TNF-alpha

trimer:TNF-R1

trimer
R-HSA-5634221 (Reactome)
TNF-alpha

trimer:TNF-R1

trimer
R-HSA-83656 (Reactome)
TNF-alpha trimer, soluble formArrowR-HSA-3371385 (Reactome)
TNF-alpha trimer, soluble formR-HSA-3371353 (Reactome)
TNF-alpha:TNFR1:DENN-SV,MADDArrowR-HSA-5626953 (Reactome)
TNF-alpha:TNFR1:NSMAF:GNB2L1:SMPD2,3ArrowR-HSA-5626981 (Reactome)
TNF-alpha:TNFR1:NSMAF:GNB2L1ArrowR-HSA-5626982 (Reactome)
TNF-alpha:TNFR1:NSMAF:GNB2L1R-HSA-5626981 (Reactome)
TNF-alpha:TNFR1:NSMAFArrowR-HSA-5626988 (Reactome)
TNF-alpha:TNFR1:NSMAFR-HSA-5626982 (Reactome)
TNF-alpha:TNFR1:TRADD:K63polyUb-RIPK1:BIRC2,3,4:TAX1BP1:TNFAIP3ArrowR-HSA-5693055 (Reactome)
TNF-alpha:TNFR1:TRADD:K63polyUb-RIPK1:BIRC2,3,4ArrowR-HSA-5357757 (Reactome)
TNF-alpha:TNFR1:TRADD:K63polyUb-RIPK1:BIRC2,3,4R-HSA-5357845 (Reactome)
TNF-alpha:TNFR1:TRADD:K63polyUb-RIPK1:BIRC2,3,4R-HSA-5357860 (Reactome)
TNF-alpha:TNFR1:TRADD:K63polyUb-RIPK1:BIRC2,3,4R-HSA-5357904 (Reactome)
TNF-alpha:TNFR1:TRADD:K63polyUb-RIPK1:BIRC2,3,4R-HSA-5357928 (Reactome)
TNF-alpha:TNFR1:TRADD:K63polyUb-RIPK1:BIRC2,3,4R-HSA-5693055 (Reactome)
TNF-alpha:TNFR1:TRADD:RIP1:TRAF2:BIRC2/3ArrowR-HSA-5357780 (Reactome)
TNF-alpha:TNFR1:TRADD:RIP1:TRAF2:BIRC2/3ArrowR-HSA-5357845 (Reactome)
TNF-alpha:TNFR1:TRADD:RIP1:TRAF2:BIRC2/3R-HSA-5357757 (Reactome)
TNF-alpha:TNFR1:TRADD:RIP1:TRAF2:BIRC2/3mim-catalysisR-HSA-5357757 (Reactome)
TNF-alpha:TNFR1:TRADD:RIPK1:TRAF2ArrowR-HSA-83656 (Reactome)
TNF-alpha:TNFR1:TRADD:RIPK1:TRAF2R-HSA-5357780 (Reactome)
TNF-alpha:TNFR1:TRADD:RIPK1:TRAF2R-HSA-83582 (Reactome)
TNF-alpha:TNFR1ArrowR-HSA-83660 (Reactome)
TNF:TNFR1:TRADD:TRAF2:BIRC2/3:K63polyUB-RIP1:LUBACArrowR-HSA-5357904 (Reactome)
TNF:TNFR1:TRADD:TRAF2:BIRC2/3:K63polyUB-RIP1:LUBACR-HSA-5357776 (Reactome)
TNF:TNFR1:TRADD:TRAF2:K63polyUb-RIP1:BIRC2/3:TAB1:TAK1:TAB2/3ArrowR-HSA-5357860 (Reactome)
TNFRSF1A:BAG4R-HSA-3371353 (Reactome)
TNFRSF1A:BAG4R-HSA-83660 (Reactome)
TNFalpha:TNF-R1:TRADD:K63polyUb-RIP1:BIRC2/3:IKKA:IKKB:NEMOArrowR-HSA-5357776 (Reactome)
TNFalpha:TNFR1:TRADD:TRAF2:TRAF1:RIPK1ArrowR-HSA-5634221 (Reactome)
TRADD:TRAF2:RIP1:FADD:CASP8(1-479)ArrowR-HSA-75240 (Reactome)
TRADD:TRAF2:RIP1:FADDArrowR-HSA-140978 (Reactome)
TRADD:TRAF2:RIP1:FADDR-HSA-75240 (Reactome)
TRADDR-HSA-5634221 (Reactome)
TRADDR-HSA-83656 (Reactome)
TRAF1(1-163)ArrowR-HSA-5634228 (Reactome)
TRAF1(164-416)ArrowR-HSA-5634228 (Reactome)
TRAF1ArrowR-HSA-5357780 (Reactome)
TRAF1R-HSA-5634221 (Reactome)
TRAF1R-HSA-5634228 (Reactome)
TRAF2:TRADD:RIP1(325-671)ArrowR-HSA-5357828 (Reactome)
TRAF2:TRADD:RIPK1ArrowR-HSA-83582 (Reactome)
TRAF2:TRADD:RIPK1R-HSA-140978 (Reactome)
TRAF2:TRADD:RIPK1R-HSA-5357828 (Reactome)
TRAF2R-HSA-5634221 (Reactome)
TRAF2R-HSA-83656 (Reactome)
UL36R-HSA-5692550 (Reactome)
UbArrowR-HSA-5357845 (Reactome)
active

caspase-8:viral

CRMA/SPI-2
ArrowR-HSA-2672196 (Reactome)
active caspase-8R-HSA-2672196 (Reactome)
active caspase-8mim-catalysisR-HSA-5357828 (Reactome)
active caspase-8mim-catalysisR-HSA-5634228 (Reactome)
p-S418-CYLDArrowR-HSA-5357831 (Reactome)
p-S418-CYLDTBarR-HSA-5357845 (Reactome)
soluble TNF-alpha:TNFR1ArrowR-HSA-3371353 (Reactome)
viral serpinsR-HSA-2672196 (Reactome)

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