ISG15 antiviral mechanism (Homo sapiens)

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2, 7, 10, 18, 354, 5, 2531, 38, 4216, 27, 30, 4140, 438, 20, 21, 44331618, 22, 3514, 29, 36, 469, 46162818, 35, 3923, 24, 2619, 32, 3412, 15, 37cytosolnucleoplasmISG15 E3 ligasesISG15 NUPL2 UBE2L6ARIH1 ISG15 EIF4E2 UBC(381-456) EIF4G3 ARIH1 AMPunknown ligaseAAAS UBC(609-684) HERC5 IFIT1 monoubiquitinatedN-myristoyl GAG(P12493) proteinEIF4A3 PLCG1 UBC(305-380) EIF2AK2 PIN1 UBC(305-380) EIF4FN-myristoyl GAG (P12493) protein E2 congugatingenzymesUBA52(1-76) UBA7 DDX58 UBC(77-152) RAE1 TPR EIF4A2 ISG15 targetsHERC5 KPNB1 UBE2L6 ISG15 E3 ligasesUSP41 UBE2L6 ISGylated hostproteinsISG15:UBA7HERC5 NDC1 ISG15 EIF4E ISGylated IRF3UBE2L6UBB(153-228) UBA7PPiPPiNUP107 PPiUBE2E1 p-IRF3 dimer:PIN1NUP62 UBE2L6 ISG15:NEDD4ARIH1 AMPPPiNUP160 ISG15:UBCH8:ISG15 E3ligaseISGylated NS1HERC5 TRIM25 TRIM25 UBB(153-228) HERC5 UBC(381-456) EIF4G1 UBC(229-304) UBC(609-684) NS1 UBE2L6NS1homodimer:ImportinMAPK3 ISG15:UBCH8NS1 dimerUBC(229-304) EIF4E2UBE2N Importin alpha EIF4E3 EIF4A1 ISG15 Mx GTPases STAT1 IRF3NUP54 HERC5 RPS27A(1-76) ISGylated E2conjugating enzymesCeruloplasmin mRNA AMPIRF3 EIF4A2 NUP210 PLCG1 ATPNEDD4UBE2L6UBC(153-228) ISG15 NUP153 USP18 ISG15 ARIH1 UBA52(1-76) ISG15 ARIH1 NUP188 UbNUP205 ISG15PPM1BTRIM25 ATPUBC(533-608) NS1 POM121C ARIH1 NUP35 AMPISGylated hostproteinsUBC(1-76) UBE2E1 Nuclear Pore Complex(NPC)polypeptideUBE2L6 PPiJAK1 NUP98-3 HERC5 NUP155 NUP85 JAK1 EIF4E2 UBC(153-228) UBE2L6UBE2L6 NUPL1-2 POM121 ISG15:UBCH8:ISG15 E3ligaseTRIM25 UBB(1-76) ISGylated Filamin BEIF4E TRIM25 PIN1STAT1 ATPNUP98-4 KPNB1 ISG15 p-5S,T404-IRF3 Importin alpha HERC5 UBC(457-532) ARIH1 Mx GTPases DDX58 ISG15 UBE2L6UBC(77-152) ISG15:UBCH8:ISG15 E3ligaseN-myristoyl GAG(P12493) proteinDDX58 ISG15 JAK1 TRIM25 ISG15 NS1 UBB(77-152) ISG15 ARIH1 eIF4F:mRNAEIF4E3 SEH1L-2 ISG15 E3 ligasesFLNBUBE2L6 ISG15 USP18-like proteinsNUP43 STAT1 TRIM25 PPM1B UBC(457-532) TRIM25 NUP88 NUP98-5 UBB(1-76) RPS27A(1-76) NUP214 ISG15 E3 ligasesISGylated PP2CBEIF4G1 NEDD4 EIF4G3 TRIM25 ISGylated 4EHPFLNB NUP37 UBE2N NUP50 ARIH1 EIF4A1 ISG15 ISG15:UBCH8:ISG15 E3ligaseTRIM25 EIF4G2 ImportinATPHERC5 PPiHERC5 Mx GTPases UBE2E1 ATPNup45 MAPK3 IFIT1 NUP93 UBE2E1 Ceruloplasmin mRNA ATPEIF2AK2 ARIH1 UBE2L6 IFIT1 EIF4G2 ISG15 MAPK3 UBB(77-152) UBC(533-608) ISGylated 4EHP:mRNAUBC(1-76) UBE2E1 PLCG1 EIF4A3 ISG15 EIF2AK2 RANBP2 NUP133 AMP61, 11, 13, 45317633336


Interferon-stimulated gene 15 (ISG15) is a member of the ubiquitin-like (Ubl) family. It is strongly induced upon exposure to type I Interferons (IFNs), viruses, bacterial LPS, and other stresses. Once released the mature ISG15 conjugates with an array of target proteins, a process termed ISGylation. ISGylation utilizes a mechanism similar to ubiquitination, requiring a three-step enzymatic cascade. UBE1L is the ISG15 E1 activating enzyme which specifically activates ISG15 at the expense of ATP. ISG15 is then transfered from E1 to the E2 conjugating enzyme UBCH8 and then to the target protein with the aid of an ISG15 E3 ligase, such as HERC5 and EFP. Hundreds of target proteins for ISGylation have been identified. Several proteins that are part of antiviral signaling pathways, such as RIG-I, MDA5, Mx1, PKR, filamin B, STAT1, IRF3 and JAK1, have been identified as targets for ISGylation. ISG15 also conjugates some viral proteins, inhibiting viral budding and release. ISGylation appears to act either by disrupting the activity of a target protein and/or by altering its localization within the cell. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 1169408
Reactome version: 66
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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  1. Ori A, Banterle N, Iskar M, Iskar M, Andrés-Pons A, Escher C, Khanh Bui H, Sparks L, Solis-Mezarino V, Rinner O, Bork P, Lemke EA, Beck M.; ''Cell type-specific nuclear pores: a case in point for context-dependent stoichiometry of molecular machines.''; PubMed Europe PMC Scholia
  2. Dao CT, Zhang DE.; ''ISG15: a ubiquitin-like enigma.''; PubMed Europe PMC Scholia
  3. Plafker SM, Plafker KS, Weissman AM, Macara IG.; ''Ubiquitin charging of human class III ubiquitin-conjugating enzymes triggers their nuclear import.''; PubMed Europe PMC Scholia
  4. Melén K, Kinnunen L, Fagerlund R, Ikonen N, Twu KY, Krug RM, Julkunen I.; ''Nuclear and nucleolar targeting of influenza A virus NS1 protein: striking differences between different virus subtypes.''; PubMed Europe PMC Scholia
  5. O'Neill RE, Jaskunas R, Blobel G, Palese P, Moroianu J.; ''Nuclear import of influenza virus RNA can be mediated by viral nucleoprotein and transport factors required for protein import.''; PubMed Europe PMC Scholia
  6. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T.; ''The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.''; PubMed Europe PMC Scholia
  7. Skaug B, Chen ZJ.; ''Emerging role of ISG15 in antiviral immunity.''; PubMed Europe PMC Scholia
  8. Malakhova OA, Zhang DE.; ''ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response.''; PubMed Europe PMC Scholia
  9. Giannakopoulos NV, Arutyunova E, Lai C, Lenschow DJ, Haas AL, Virgin HW.; ''ISG15 Arg151 and the ISG15-conjugating enzyme UbE1L are important for innate immune control of Sindbis virus.''; PubMed Europe PMC Scholia
  10. Jeon YJ, Yoo HM, Chung CH.; ''ISG15 and immune diseases.''; PubMed Europe PMC Scholia
  11. Cronshaw JM, Krutchinsky AN, Zhang W, Chait BT, Matunis MJ.; ''Proteomic analysis of the mammalian nuclear pore complex.''; PubMed Europe PMC Scholia
  12. Versteeg GA, Hale BG, van Boheemen S, Wolff T, Lenschow DJ, García-Sastre A.; ''Species-specific antagonism of host ISGylation by the influenza B virus NS1 protein.''; PubMed Europe PMC Scholia
  13. Rabut G, Doye V, Ellenberg J.; ''Mapping the dynamic organization of the nuclear pore complex inside single living cells.''; PubMed Europe PMC Scholia
  14. Kim KI, Giannakopoulos NV, Virgin HW, Zhang DE.; ''Interferon-inducible ubiquitin E2, Ubc8, is a conjugating enzyme for protein ISGylation.''; PubMed Europe PMC Scholia
  15. Zhao C, Hsiang TY, Kuo RL, Krug RM.; ''ISG15 conjugation system targets the viral NS1 protein in influenza A virus-infected cells.''; PubMed Europe PMC Scholia
  16. Okumura F, Zou W, Zhang DE.; ''ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHP.''; PubMed Europe PMC Scholia
  17. Fontoura BM, Blobel G, Matunis MJ.; ''A conserved biogenesis pathway for nucleoporins: proteolytic processing of a 186-kilodalton precursor generates Nup98 and the novel nucleoporin, Nup96.''; PubMed Europe PMC Scholia
  18. Malakhov MP, Kim KI, Malakhova OA, Jacobs BS, Borden EC, Zhang DE.; ''High-throughput immunoblotting. Ubiquitiin-like protein ISG15 modifies key regulators of signal transduction.''; PubMed Europe PMC Scholia
  19. Zou W, Papov V, Malakhova O, Kim KI, Dao C, Li J, Zhang DE.; ''ISG15 modification of ubiquitin E2 Ubc13 disrupts its ability to form thioester bond with ubiquitin.''; PubMed Europe PMC Scholia
  20. Okumura A, Pitha PM, Harty RN.; ''ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activity.''; PubMed Europe PMC Scholia
  21. Harty RN, Brown ME, Wang G, Huibregtse J, Hayes FP.; ''A PPxY motif within the VP40 protein of Ebola virus interacts physically and functionally with a ubiquitin ligase: implications for filovirus budding.''; PubMed Europe PMC Scholia
  22. Jeon YJ, Choi JS, Lee JY, Yu KR, Kim SM, Ka SH, Oh KH, Kim KI, Zhang DE, Bang OS, Chung CH.; ''ISG15 modification of filamin B negatively regulates the type I interferon-induced JNK signalling pathway.''; PubMed Europe PMC Scholia
  23. Saitoh T, Tun-Kyi A, Ryo A, Yamamoto M, Finn G, Fujita T, Akira S, Yamamoto N, Lu KP, Yamaoka S.; ''Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1.''; PubMed Europe PMC Scholia
  24. Tsuchida T, Kawai T, Akira S.; ''Inhibition of IRF3-dependent antiviral responses by cellular and viral proteins.''; PubMed Europe PMC Scholia
  25. Cros JF, García-Sastre A, Palese P.; ''An unconventional NLS is critical for the nuclear import of the influenza A virus nucleoprotein and ribonucleoprotein.''; PubMed Europe PMC Scholia
  26. Goutagny N, Severa M, Fitzgerald KA.; ''Pin-ning down immune responses to RNA viruses.''; PubMed Europe PMC Scholia
  27. Wong JJ, Pung YF, Sze NS, Chin KC.; ''HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets.''; PubMed Europe PMC Scholia
  28. Malakhov MP, Malakhova OA, Kim KI, Ritchie KJ, Zhang DE.; ''UBP43 (USP18) specifically removes ISG15 from conjugated proteins.''; PubMed Europe PMC Scholia
  29. Zhao C, Beaudenon SL, Kelley ML, Waddell MB, Yuan W, Schulman BA, Huibregtse JM, Krug RM.; ''The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFN-alpha/beta-induced ubiquitin-like protein.''; PubMed Europe PMC Scholia
  30. Dastur A, Beaudenon S, Kelley M, Krug RM, Huibregtse JM.; ''Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells.''; PubMed Europe PMC Scholia
  31. Ott DE, Coren LV, Chertova EN, Gagliardi TD, Schubert U.; ''Ubiquitination of HIV-1 and MuLV Gag.''; PubMed Europe PMC Scholia
  32. Takeuchi T, Iwahara S, Saeki Y, Sasajima H, Yokosawa H.; ''Link between the ubiquitin conjugation system and the ISG15 conjugation system: ISG15 conjugation to the UbcH6 ubiquitin E2 enzyme.''; PubMed Europe PMC Scholia
  33. Takeuchi T, Kobayashi T, Tamura S, Yokosawa H.; ''Negative regulation of protein phosphatase 2Cbeta by ISG15 conjugation.''; PubMed Europe PMC Scholia
  34. Takeuchi T, Yokosawa H.; ''ISG15 modification of Ubc13 suppresses its ubiquitin-conjugating activity.''; PubMed Europe PMC Scholia
  35. Zhao C, Denison C, Huibregtse JM, Gygi S, Krug RM.; ''Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways.''; PubMed Europe PMC Scholia
  36. Yuan W, Krug RM.; ''Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein.''; PubMed Europe PMC Scholia
  37. Tang Y, Zhong G, Zhu L, Liu X, Shan Y, Feng H, Bu Z, Chen H, Wang C.; ''Herc5 attenuates influenza A virus by catalyzing ISGylation of viral NS1 protein.''; PubMed Europe PMC Scholia
  38. Gottwein E, Jäger S, Habermann A, Kräusslich HG.; ''Cumulative mutations of ubiquitin acceptor sites in human immunodeficiency virus type 1 gag cause a late budding defect.''; PubMed Europe PMC Scholia
  39. Giannakopoulos NV, Luo JK, Papov V, Zou W, Lenschow DJ, Jacobs BS, Borden EC, Li J, Virgin HW, Zhang DE.; ''Proteomic identification of proteins conjugated to ISG15 in mouse and human cells.''; PubMed Europe PMC Scholia
  40. Lu G, Reinert JT, Pitha-Rowe I, Okumura A, Kellum M, Knobeloch KP, Hassel B, Pitha PM.; ''ISG15 enhances the innate antiviral response by inhibition of IRF-3 degradation.''; PubMed Europe PMC Scholia
  41. Zou W, Zhang DE.; ''The interferon-inducible ubiquitin-protein isopeptide ligase (E3) EFP also functions as an ISG15 E3 ligase.''; PubMed Europe PMC Scholia
  42. Ott DE, Coren LV, Copeland TD, Kane BP, Johnson DG, Sowder RC, Yoshinaka Y, Oroszlan S, Arthur LO, Henderson LE.; ''Ubiquitin is covalently attached to the p6Gag proteins of human immunodeficiency virus type 1 and simian immunodeficiency virus and to the p12Gag protein of Moloney murine leukemia virus.''; PubMed Europe PMC Scholia
  43. Shi HX, Yang K, Liu X, Liu XY, Wei B, Shan YF, Zhu LH, Wang C.; ''Positive regulation of interferon regulatory factor 3 activation by Herc5 via ISG15 modification.''; PubMed Europe PMC Scholia
  44. Licata JM, Simpson-Holley M, Wright NT, Han Z, Paragas J, Harty RN.; ''Overlapping motifs (PTAP and PPEY) within the Ebola virus VP40 protein function independently as late budding domains: involvement of host proteins TSG101 and VPS-4.''; PubMed Europe PMC Scholia
  45. Suntharalingam M, Wente SR.; ''Peering through the pore: nuclear pore complex structure, assembly, and function.''; PubMed Europe PMC Scholia
  46. Durfee LA, Kelley ML, Huibregtse JM.; ''The basis for selective E1-E2 interactions in the ISG15 conjugation system.''; PubMed Europe PMC Scholia


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101627view11:49, 1 November 2018ReactomeTeamreactome version 66
101163view21:35, 31 October 2018ReactomeTeamreactome version 65
100689view20:08, 31 October 2018ReactomeTeamreactome version 64
100239view16:53, 31 October 2018ReactomeTeamreactome version 63
99791view15:19, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99342view12:48, 31 October 2018ReactomeTeamreactome version 62
93922view13:45, 16 August 2017ReactomeTeamreactome version 61
93501view11:25, 9 August 2017ReactomeTeamreactome version 61
87866view12:08, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86596view09:21, 11 July 2016ReactomeTeamreactome version 56
83071view09:51, 18 November 2015ReactomeTeamVersion54
81388view12:55, 21 August 2015ReactomeTeamVersion53
76856view08:13, 17 July 2014ReactomeTeamFixed remaining interactions
76561view11:54, 16 July 2014ReactomeTeamFixed remaining interactions
75894view09:55, 11 June 2014ReactomeTeamRe-fixing comment source
75594view10:43, 10 June 2014ReactomeTeamReactome 48 Update
74949view13:47, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74593view08:38, 30 April 2014ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
AAAS ProteinQ9NRG9 (Uniprot-TrEMBL)
AMPMetaboliteCHEBI:16027 (ChEBI)
ARIH1 ProteinQ9Y4X5 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ceruloplasmin mRNA ProteinM13699 (EMBL)
DDX58 ProteinO95786 (Uniprot-TrEMBL)
E2 congugating enzymesComplexR-HSA-1169378 (Reactome)
EIF2AK2 ProteinP19525 (Uniprot-TrEMBL)
EIF4A1 ProteinP60842 (Uniprot-TrEMBL)
EIF4A2 ProteinQ14240 (Uniprot-TrEMBL)
EIF4A3 ProteinP38919 (Uniprot-TrEMBL)
EIF4E ProteinP06730 (Uniprot-TrEMBL)
EIF4E2 ProteinO60573 (Uniprot-TrEMBL)
EIF4E2ProteinO60573 (Uniprot-TrEMBL)
EIF4E3 ProteinQ8N5X7 (Uniprot-TrEMBL)
EIF4FComplexR-HSA-1678832 (Reactome)
EIF4G1 ProteinQ04637 (Uniprot-TrEMBL)
EIF4G2 ProteinP78344 (Uniprot-TrEMBL)
EIF4G3 ProteinO43432 (Uniprot-TrEMBL)
FLNB ProteinO75369 (Uniprot-TrEMBL)
FLNBProteinO75369 (Uniprot-TrEMBL)
HERC5 ProteinQ9UII4 (Uniprot-TrEMBL)
IFIT1 ProteinP09914 (Uniprot-TrEMBL)
IRF3 ProteinQ14653 (Uniprot-TrEMBL)
IRF3ProteinQ14653 (Uniprot-TrEMBL)
ISG15 E3 ligasesComplexR-HSA-1169381 (Reactome)
ISG15 ProteinP05161 (Uniprot-TrEMBL)
ISG15 targetsComplexR-HSA-1169379 (Reactome)
ISG15:NEDD4ComplexR-HSA-1169384 (Reactome)
ISG15:UBA7ComplexR-HSA-1169390 (Reactome)
ISG15:UBCH8:ISG15 E3 ligaseComplexR-HSA-1169383 (Reactome)
ISG15:UBCH8ComplexR-HSA-1169385 (Reactome)
ISG15ProteinP05161 (Uniprot-TrEMBL)
ISGylated 4EHP:mRNAComplexR-HSA-1678836 (Reactome)
ISGylated 4EHPComplexR-HSA-1678834 (Reactome)
ISGylated E2 conjugating enzymesComplexR-HSA-1169382 (Reactome)
ISGylated Filamin BComplexR-HSA-1169388 (Reactome)
ISGylated IRF3ComplexR-HSA-1169389 (Reactome)
ISGylated NS1ComplexR-HSA-1169392 (Reactome)
ISGylated PP2CBComplexR-HSA-1169391 (Reactome)
ISGylated host proteinsComplexR-HSA-1169387 (Reactome)
Importin alpha R-HSA-1176065 (Reactome)
Importin alpha R-HSA-1176071 (Reactome)
ImportinComplexR-HSA-1176060 (Reactome)
JAK1 ProteinP23458 (Uniprot-TrEMBL)
KPNB1 ProteinQ14974 (Uniprot-TrEMBL)
MAPK3 ProteinP27361 (Uniprot-TrEMBL)
Mx GTPases R-HSA-1015693 (Reactome)
N-myristoyl GAG (P12493) proteinProteinP12493 (Uniprot-TrEMBL)
N-myristoyl GAG (P12493) protein ProteinP12493 (Uniprot-TrEMBL)
NDC1 ProteinQ9BTX1 (Uniprot-TrEMBL)
NEDD4 ProteinP46934 (Uniprot-TrEMBL)
NEDD4ProteinP46934 (Uniprot-TrEMBL)
NS1 homodimer:ImportinComplexR-HSA-1176067 (Reactome)
NS1 ProteinP03496 (Uniprot-TrEMBL)
NS1 dimerComplexR-FLU-169143 (Reactome)
NUP107 ProteinP57740 (Uniprot-TrEMBL)
NUP133 ProteinQ8WUM0 (Uniprot-TrEMBL)
NUP153 ProteinP49790 (Uniprot-TrEMBL)
NUP155 ProteinO75694 (Uniprot-TrEMBL)
NUP160 ProteinQ12769 (Uniprot-TrEMBL)
NUP188 ProteinQ5SRE5 (Uniprot-TrEMBL)
NUP205 ProteinQ92621 (Uniprot-TrEMBL)
NUP210 ProteinQ8TEM1 (Uniprot-TrEMBL)
NUP214 ProteinP35658 (Uniprot-TrEMBL)
NUP35 ProteinQ8NFH5 (Uniprot-TrEMBL)
NUP37 ProteinQ8NFH4 (Uniprot-TrEMBL)
NUP43 ProteinQ8NFH3 (Uniprot-TrEMBL)
NUP50 ProteinQ9UKX7 (Uniprot-TrEMBL)
NUP54 ProteinQ7Z3B4 (Uniprot-TrEMBL)
NUP62 ProteinP37198 (Uniprot-TrEMBL)
NUP85 ProteinQ9BW27 (Uniprot-TrEMBL)
NUP88 ProteinQ99567 (Uniprot-TrEMBL)
NUP93 ProteinQ8N1F7 (Uniprot-TrEMBL)
NUP98-3 ProteinP52948-3 (Uniprot-TrEMBL)
NUP98-4 ProteinP52948-4 (Uniprot-TrEMBL)
NUP98-5 ProteinP52948-5 (Uniprot-TrEMBL)
NUPL1-2 ProteinQ9BVL2-1 (Uniprot-TrEMBL)
NUPL2 ProteinO15504 (Uniprot-TrEMBL)
Nuclear Pore Complex (NPC)ComplexR-HSA-157689 (Reactome)
Nup45 ProteinQ9BVL2-2 (Uniprot-TrEMBL)
PIN1 ProteinQ13526 (Uniprot-TrEMBL)
PIN1ProteinQ13526 (Uniprot-TrEMBL)
PLCG1 ProteinP19174 (Uniprot-TrEMBL)
POM121 ProteinQ96HA1 (Uniprot-TrEMBL)
POM121C ProteinA8CG34 (Uniprot-TrEMBL)
PPM1B ProteinO75688 (Uniprot-TrEMBL)
PPM1BProteinO75688 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
RAE1 ProteinP78406 (Uniprot-TrEMBL)
RANBP2 ProteinP49792 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SEH1L-2 ProteinQ96EE3-2 (Uniprot-TrEMBL)
STAT1 ProteinP42224 (Uniprot-TrEMBL)
TPR ProteinP12270 (Uniprot-TrEMBL)
TRIM25 ProteinQ14258 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBA7 ProteinP41226 (Uniprot-TrEMBL)
UBA7ProteinP41226 (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)
UBE2E1 ProteinP51965 (Uniprot-TrEMBL)
UBE2L6 ProteinO14933 (Uniprot-TrEMBL)
UBE2L6ProteinO14933 (Uniprot-TrEMBL)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
USP18 ProteinQ9UMW8 (Uniprot-TrEMBL)
USP18-like proteinsComplexR-HSA-4127442 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
USP41 ProteinQ3LFD5 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
eIF4F:mRNAComplexR-HSA-72585 (Reactome)

N-myristoyl GAG

(P12493) protein
ComplexR-HSA-184273 (Reactome)
p-5S,T404-IRF3 ProteinQ14653 (Uniprot-TrEMBL)
p-IRF3 dimer:PIN1ComplexR-HSA-936444 (Reactome)
polypeptideR-ALL-141681 (Reactome)
unknown ligaseR-HSA-5244779 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
AMPArrowR-HSA-1169394 (Reactome)
AMPArrowR-HSA-1169395 (Reactome)
AMPArrowR-HSA-1169397 (Reactome)
AMPArrowR-HSA-1169398 (Reactome)
AMPArrowR-HSA-1169402 (Reactome)
AMPArrowR-HSA-1169405 (Reactome)
AMPArrowR-HSA-1169406 (Reactome)
ATPR-HSA-1169394 (Reactome)
ATPR-HSA-1169395 (Reactome)
ATPR-HSA-1169397 (Reactome)
ATPR-HSA-1169398 (Reactome)
ATPR-HSA-1169402 (Reactome)
ATPR-HSA-1169405 (Reactome)
ATPR-HSA-1169406 (Reactome)
E2 congugating enzymesR-HSA-1169402 (Reactome)
EIF4E2R-HSA-1678843 (Reactome)
EIF4FArrowR-HSA-1678842 (Reactome)
FLNBR-HSA-1169398 (Reactome)
IRF3R-HSA-1169394 (Reactome)
ISG15 E3 ligasesArrowR-HSA-1169394 (Reactome)
ISG15 E3 ligasesArrowR-HSA-1169395 (Reactome)
ISG15 E3 ligasesArrowR-HSA-1169398 (Reactome)
ISG15 E3 ligasesArrowR-HSA-1169402 (Reactome)
ISG15 E3 ligasesArrowR-HSA-1169405 (Reactome)
ISG15 E3 ligasesArrowR-HSA-1169406 (Reactome)
ISG15 E3 ligasesR-HSA-1169403 (Reactome)
ISG15 targetsArrowR-HSA-1678841 (Reactome)
ISG15 targetsR-HSA-1169406 (Reactome)
ISG15:NEDD4ArrowR-HSA-1169399 (Reactome)
ISG15:UBA7ArrowR-HSA-1169397 (Reactome)
ISG15:UBA7R-HSA-1169404 (Reactome)
ISG15:UBCH8:ISG15 E3 ligaseArrowR-HSA-1169403 (Reactome)
ISG15:UBCH8:ISG15 E3 ligaseR-HSA-1169394 (Reactome)
ISG15:UBCH8:ISG15 E3 ligaseR-HSA-1169395 (Reactome)
ISG15:UBCH8:ISG15 E3 ligaseR-HSA-1169398 (Reactome)
ISG15:UBCH8:ISG15 E3 ligaseR-HSA-1169402 (Reactome)
ISG15:UBCH8:ISG15 E3 ligaseR-HSA-1169405 (Reactome)
ISG15:UBCH8:ISG15 E3 ligaseR-HSA-1169406 (Reactome)
ISG15:UBCH8:ISG15 E3 ligaseR-HSA-1678843 (Reactome)
ISG15:UBCH8:ISG15 E3 ligasemim-catalysisR-HSA-1169394 (Reactome)
ISG15:UBCH8:ISG15 E3 ligasemim-catalysisR-HSA-1169395 (Reactome)
ISG15:UBCH8:ISG15 E3 ligasemim-catalysisR-HSA-1169398 (Reactome)
ISG15:UBCH8:ISG15 E3 ligasemim-catalysisR-HSA-1169402 (Reactome)
ISG15:UBCH8:ISG15 E3 ligasemim-catalysisR-HSA-1169405 (Reactome)
ISG15:UBCH8:ISG15 E3 ligasemim-catalysisR-HSA-1169406 (Reactome)
ISG15:UBCH8ArrowR-HSA-1169404 (Reactome)
ISG15:UBCH8R-HSA-1169403 (Reactome)
ISG15R-HSA-1169397 (Reactome)
ISG15R-HSA-1169399 (Reactome)
ISG15TBarR-HSA-1169307 (Reactome)
ISGylated 4EHP:mRNAArrowR-HSA-1678842 (Reactome)
ISGylated 4EHPArrowR-HSA-1678843 (Reactome)
ISGylated 4EHPR-HSA-1678842 (Reactome)
ISGylated E2 conjugating enzymesArrowR-HSA-1169402 (Reactome)
ISGylated Filamin BArrowR-HSA-1169398 (Reactome)
ISGylated IRF3ArrowR-HSA-1169394 (Reactome)
ISGylated IRF3TBarR-HSA-936462 (Reactome)
ISGylated NS1ArrowR-HSA-1169395 (Reactome)
ISGylated NS1TBarR-HSA-1176059 (Reactome)
ISGylated PP2CBArrowR-HSA-1169405 (Reactome)
ISGylated host proteinsArrowR-HSA-1169406 (Reactome)
ISGylated host proteinsR-HSA-1678841 (Reactome)
ImportinR-HSA-1176059 (Reactome)
N-myristoyl GAG (P12493) proteinR-HSA-1169307 (Reactome)
NEDD4R-HSA-1169399 (Reactome)
NS1 homodimer:ImportinArrowR-HSA-1176059 (Reactome)
NS1 dimerR-HSA-1169395 (Reactome)
NS1 dimerR-HSA-1176059 (Reactome)
Nuclear Pore Complex (NPC)mim-catalysisR-HSA-1176059 (Reactome)
PIN1ArrowR-HSA-936462 (Reactome)
PPM1BR-HSA-1169405 (Reactome)
PPiArrowR-HSA-1169394 (Reactome)
PPiArrowR-HSA-1169395 (Reactome)
PPiArrowR-HSA-1169397 (Reactome)
PPiArrowR-HSA-1169398 (Reactome)
PPiArrowR-HSA-1169402 (Reactome)
PPiArrowR-HSA-1169405 (Reactome)
PPiArrowR-HSA-1169406 (Reactome)
R-HSA-1169307 (Reactome) Cytosolic N-myristoyl Gag polyprotein is conjugated with a single molecule of ubiquitin. Conjugation is typically to one of two lysine residues in the p6 domain of Gag but can be to lysine residues in the MA, CA, NC, and SP2 domains of the protein. The specific host cell E2 and E3 proteins that mediate Gag ubiquitination have not been identified. The same studies that first identified the p6 ubiquitination sites in Gag also called the biological significance of Gag ubiquitination into question by demonstrating that Gag proteins in which the p6 ubiquitination sites had been removed by mutagenesis could still assemble efficiently into infectious viral particles (Ott et al. 1998, 2000). More recent work, however, has identified additional ubiquitination sites throughout the C-terminal region of the Gag polyprotein, and when all of these sites are removed by mutagenesis, both viral assembly involving the mutant Gag polyprotein and infectivity of the resulting viral particles are sharply reduced (Gottwein et al. 2006). Note: Reactions directly involving interactions of human host proteins with foreign ones are highlighted in red.
R-HSA-1169394 (Reactome) The transcription factor IRF3 is a target for ISGylation. Conjugation of ISG15 positively regulates IRF3 and thereby promotes induction of type I interferons. ISGylation of IRF3 prevents the binding of PIN1, a protein that promotes IRF3 ubiquitination and subsequent degradation.
R-HSA-1169395 (Reactome) Some viral proteins are also targeted for ISGylation. The well studied viral protein ISGylation is the modification of the influenza A viral protein NS1, which functions as an IFN antagonist during viral infection. Studies identified seven lysine residues in NS1 as potential ISGylation sites among which K41 (Zhao et al. 2010), K126 and K217 (Tang et al. 2010) were found to be critical. ISGylation at these sites disrupts NS1 association with importin-alpha, a protein required for the nuclear import of NS1.
R-HSA-1169397 (Reactome) Ubiquitin ligase UBE1L is the ISG15 activating enzyme. UBE1L activates ISG15 in an ATP-dependent process that links UBE1L to ISG15 via a thioester bond. Arginine 153 (R153) in human ISG15 is identified as the key residue for ISG15 and UBE1L's interaction.
R-HSA-1169398 (Reactome) ISG15 negatively regulates the scaffold protein filamin B. In response to type I IFNs, filamin B recruits RAC1, MEKK1, and MKK4, enhancing their sequential activation and thereby promoting JNK activation and apoptosis. ISGylation of filamin B leads to the disassociation of RAC1, MEKK1, and MKK4 from the scaffold, preventing type I IFN dependent JNK activation and apoptosis. It has been suggested that this inhibition of apoptosis may protect uninfected bystander cells from IFN-mediated apoptosis (Jeon et al, 2009).
R-HSA-1169399 (Reactome) Ebola virus VP40 virus-like particles (VLPs) requires the interaction of overlapping L-domains in the VP40 protein with host NEDD4 protein for efficient budding. Mono-ubiquitination of VP40 mediated by the NEDD4 E3 ligase is thought to be required for virus budding and release. ISG15 interacts with NEDD4 and inhibits the transfer of ubiquitin from the E2 enzyme to NEDD4. This prevents NEDD4-mediated ubiquitination of Ebola virus VP40 which is required for virion release.
R-HSA-1169402 (Reactome) Ubiquitin conjugating E2 enzymes UBC13 and UBCH6 are targets for ISGylation. This suppresses the ubiquitin-conjugating activity of both UBC13 and UBCH6. This modification may play an important role in the control of signal transduction pathways, such as the NF-kB pathway, which are associated with K63-linked polyubiquitination (Takeuchi et al, 2005).
R-HSA-1169403 (Reactome) Ubiquitin ligase HERC5/CEB1 appears to be the predominant E3 ligase for ISGylation; EFP and HHARI/ARIH1 have also been reported as ISG15 E3 ligases. The E3 ligase recognizes specific target substrates and mediates the transfer of ISG15 from E2 to the substrate.
R-HSA-1169404 (Reactome) Activated ISG15 linked to UBE1L is transferred to the E2 conjugating enzyme UBCH8.
R-HSA-1169405 (Reactome) Protein phosphatase 1 beta (PPM1B/PP2CB) is a target for ISG15. PP2CB dephosphorylates TAK1 and suppresses TAK1/TAB1-mediated IkB alpha degradation and thereby controls the NF-kB signaling pathway, which plays a critical role in innate and adaptive immunity and cancer. ISGylation of PP2CB may block the suppressive function of the phosphatase against TAK1/TAB1 mediated NF-kB activation.
R-HSA-1169406 (Reactome) Many host proteins are targets for ISGylation including constitutively expressed proteins involved in various cellular pathways such as immunity, RNA splicing, chromatin remodeling/polymerase II transcription, stress responses and translation. Many ISG15 target proteins are IFN alpha/beta-induced antiviral proteins such as PKR, MxA, IRF3, and RIG-I, also included are several key regulators of signal transduction such as PLC gamma1, JAK1, STAT1 and ERK1. The contribution of most of these modified proteins to antiviral activity is unclear because the fate of the vast majority of ISGylated target proteins is unknown.
R-HSA-1176059 (Reactome) Influenza A virus nonstructural protein 1 (NS1A) is a multifunctional protein that exists as a dimer and is involved in the inhibition of host cell antiviral pre-mRNA processing and counteracts host cell antiviral responses. Unlike most other RNA viruses, influenza viruses replicate in the nucleus of the host cells. NS1A protein carries two nuclear localization signal (NLS) elements and these sequence elements are recognized by importin-alpha/beta. In the cytoplasm NS1A binds to importin-alpha/beta and these protein complexes are then translocated into the nucleus through the nuclear pore complex (NPC). Note:Reactions directly involving interactions of human host proteins with foreign ones are highlighted in red.
R-HSA-1678841 (Reactome) Ubiquitin specific protease 18 (USP18/UBP43) is the major ISG15 deconjugating enzyme. It removes ISG15 from ISGylated proteins. ISG15-specific protease activity of this enzyme is crucial for proper cellular balance of ISG15-conjugated proteins. However, it is not required for processing pre-ISG15 to the mature form. Furthermore, USP18 inhibits type I interferon signaling independent of its ISG15 deconjugating enzyme activity. Several viral proteins were also reported with de-ISGylation activity.
R-HSA-1678842 (Reactome) Eukaryotic translation initiation factor 4F (eIF4F) is a protein complex that mediates recruitment of ribosomes to mRNA (Gingras et al. 1999). eIF4F contains complex of cap-binding protein eIF4E, scaffold protein eIF4G, and RNA helicase eIF4A. There are three eIF4E-family members in mammals termed eIF4E-1 (eIF4E), eIF4E2 (4EHP), and eIF4E3, of which both eIF4E and eIF4E3 are able to bind to eIF4G to facilitate translation initiation. However, 4EHP does not interact with eIF4G and thus cannot function in ribosome recruitment. 4EHP competes with eIF4E or eIF4E3 for binding to the RNA 5? cap structure and prevents translation initiation. ISGylated 4EHP has a much higher cap structure binding activity, suggesting a regulatory function of ISGylation in protein translation during immune responses (Okumura et al. 2007, Joshi et al. 2004).
R-HSA-1678843 (Reactome) 4EHP is a member of eukaryotic translation initiation factor 4E (eIF4E) family that acts as an mRNA 5' cap structure-binding protein and suppresses translation. 4EHP is one of the targets of ISG15 and ISGylated 4EHP has a much higher cap structure-binding activity.
R-HSA-936462 (Reactome) PIN1 acts as a negative regulator of IFN induction. Its association with IRF3 leads to ubiquitin-mediated proteosomal degradation of IRF3. PIN1 on its own does not have ubiquitin activation, transfer or ligase activities. Exactly how this IRF3 degradation is achieved is unclear at present. Immunoprecipitation of ubiquitin followed by immunoblot analysis for IRF3 demonstrated that polyubiquitination of IRF3 was induced by RNA stimulation and that polyubiquitination was augmented by PIN1 expression and abrogated by expression of PIN1-specific shRNA.
UBA7ArrowR-HSA-1169404 (Reactome)
UBA7R-HSA-1169397 (Reactome)
UBA7mim-catalysisR-HSA-1169397 (Reactome)
UBE2L6ArrowR-HSA-1169394 (Reactome)
UBE2L6ArrowR-HSA-1169395 (Reactome)
UBE2L6ArrowR-HSA-1169398 (Reactome)
UBE2L6ArrowR-HSA-1169402 (Reactome)
UBE2L6ArrowR-HSA-1169405 (Reactome)
UBE2L6ArrowR-HSA-1169406 (Reactome)
UBE2L6R-HSA-1169404 (Reactome)
UBE2L6mim-catalysisR-HSA-1169404 (Reactome)
USP18-like proteinsmim-catalysisR-HSA-1678841 (Reactome)
UbR-HSA-1169307 (Reactome)
eIF4F:mRNAR-HSA-1678842 (Reactome)

N-myristoyl GAG

(P12493) protein
ArrowR-HSA-1169307 (Reactome)
p-IRF3 dimer:PIN1R-HSA-936462 (Reactome)
polypeptideArrowR-HSA-1678841 (Reactome)
unknown ligasemim-catalysisR-HSA-936462 (Reactome)
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