Interleukin-1 processing (Homo sapiens)

From WikiPathways

Jump to: navigation, search
31, 2, 45666nucleoplasmcytosol2xMyri-IL1A CASP1(317-404) CASP1(317-404) Interleukin-1 familyIL1A(1-271) CASP1(298-316)CASP1(1-119)Interleukin-1 familyN-terminalpropeptidesRELA NFKB2(1-454) IL18 CASP1(120-297) IL18(1-193) NFkB ComplexIL18 IL1B(1-116) CASP1(317-404)CASP1(120-197):CASP1(317-404)CASP1(1-404)Interleukin-1 familyIL1B(117-269) CASP1(120-297) IL1B IL1A(1-112) IL18(1-36) NFKB1(1-433) Myr82K-Myr83K-IL1A IL1B(1-269) CASP1(120-297)Caspase-1 tetramerInterleukin-1 familypropeptides


The IL-1 family of cytokines that interact with the Type 1 IL-1R include IL-1α (IL1A), IL-1β (IL1B) and the IL-1 receptor antagonist protein (IL1RAP). IL1RAP is synthesized with a signal peptide and secreted as a mature protein via the classical secretory pathway. IL1A and IL1B are synthesised as cytoplasmic precursors (pro-IL1A and pro-IL1B) in activated cells. They have no signal sequence, precluding secretion via the classical ER-Golgi route (Rubartelli et al. 1990). Processing of pro-IL1B to the active form requires caspase-1 (Thornberry et al. 1992), which is itself activated by a molecular scaffold termed the inflammasome (Martinon et al. 2002). Processing and release of IL1B are thought to be closely linked, because mature IL1B is only seen inside inflammatory cells just prior to release (Brough et al. 2003). It has been reported that in monocytes a fraction of cellular IL1B is released by the regulated secretion of late endosomes and early lysosomes, and that this may represent a cellular compartment where caspase-1 processing of pro-IL1B takes place (Andrei et al. 1999). Shedding of microvesicles from the plasma membrane has also been proposed as a mechanism of secretion (MacKenzie et al. 2001). These proposals superceded previous models in which non-specific release due to cell lysis and passage through a plasma membrane pore were considered. However, there is evidence in the literature that supports all of these mechanisms and there is still controversy over how IL1B exits from cells (Brough & Rothwell 2007). A calpain-like potease has been reported to be important for the processing of pro-IL1A, but much less is known about how IL1A is released from cells and what specific roles it plays in biology. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 448706
Reactome version: 66
Reactome Author 
Reactome Author: Ray, KP

Quality Tags

Ontology Terms



View all...
  1. Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, Hayashi N, Higashino K, Okamura H, Nakanishi K, Kurimoto M, Tanimoto T, Flavell RA, Sato V, Harding MW, Livingston DJ, Su MS.; ''Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme.''; PubMed Europe PMC
  2. Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Molineaux SM, Weidner JR, Aunins J.; ''A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes.''; PubMed Europe PMC
  3. Brough D, Rothwell NJ.; ''Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death.''; PubMed Europe PMC
  4. Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, Quintal L, Sekut L, Talanian R, Paskind M, Wong W, Kamen R, Tracey D, Allen H.; ''Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production.''; PubMed Europe PMC
  5. Qu Y, Franchi L, Nunez G, Dubyak GR.; ''Nonclassical IL-1 beta secretion stimulated by P2X7 receptors is dependent on inflammasome activation and correlated with exosome release in murine macrophages.''; PubMed Europe PMC
  6. Walker NP, Talanian RV, Brady KD, Dang LC, Bump NJ, Ferenz CR, Franklin S, Ghayur T, Hackett MC, Hammill LD.; ''Crystal structure of the cysteine protease interleukin-1 beta-converting enzyme: a (p20/p10)2 homodimer.''; PubMed Europe PMC


View all...
101255view11:14, 1 November 2018ReactomeTeamreactome version 66
100794view20:42, 31 October 2018ReactomeTeamreactome version 65
100336view19:19, 31 October 2018ReactomeTeamreactome version 64
99881view16:02, 31 October 2018ReactomeTeamreactome version 63
99438view14:37, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93894view13:43, 16 August 2017ReactomeTeamreactome version 61
93467view11:24, 9 August 2017ReactomeTeamreactome version 61
86560view09:21, 11 July 2016ReactomeTeamreactome version 56
83204view10:22, 18 November 2015ReactomeTeamVersion54
77045view08:34, 17 July 2014ReactomeTeamFixed remaining interactions
76750view12:11, 16 July 2014ReactomeTeamFixed remaining interactions
76075view10:13, 11 June 2014ReactomeTeamRe-fixing comment source
75785view11:31, 10 June 2014ReactomeTeamReactome 48 Update
75135view14:08, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74782view08:52, 30 April 2014ReactomeTeamReactome46
69010view17:46, 8 July 2013MaintBotUpdated to 2013 gpml schema
44871view10:00, 6 October 2011MartijnVanIerselOntology Term : 'PW:0000512' removed !
44870view10:00, 6 October 2011MartijnVanIerselOntology Term : 'interleukin-1 signaling pathway' added !
44868view09:59, 6 October 2011MartijnVanIerselOntology Term : 'Interleukin mediated signaling pathway' added !
42002view21:30, 4 March 2011MaintBotAutomatic update
39864view05:53, 21 January 2011MaintBotNew pathway

External references


View all...
NameTypeDatabase referenceComment
2xMyri-IL1A ProteinP01583 (Uniprot-TrEMBL)
CASP1(1-119)ProteinP29466 (Uniprot-TrEMBL)
CASP1(1-404)ProteinP29466 (Uniprot-TrEMBL)
CASP1(120-197):CASP1(317-404)ComplexR-HSA-448695 (Reactome)
CASP1(120-297) ProteinP29466 (Uniprot-TrEMBL)
CASP1(120-297)ProteinP29466 (Uniprot-TrEMBL)
CASP1(298-316)ProteinP29466 (Uniprot-TrEMBL)
CASP1(317-404) ProteinP29466 (Uniprot-TrEMBL)
CASP1(317-404)ProteinP29466 (Uniprot-TrEMBL)
Caspase-1 tetramerComplexR-HSA-448691 (Reactome)
IL18 ProteinQ14116 (Uniprot-TrEMBL)
IL18(1-193) ProteinQ14116 (Uniprot-TrEMBL)
IL18(1-36) ProteinQ14116 (Uniprot-TrEMBL)
IL1A(1-112) ProteinP01583 (Uniprot-TrEMBL)
IL1A(1-271) ProteinP01583 (Uniprot-TrEMBL)
IL1B ProteinP01584 (Uniprot-TrEMBL)
IL1B(1-116) ProteinP01584 (Uniprot-TrEMBL)
IL1B(1-269) ProteinP01584 (Uniprot-TrEMBL)
IL1B(117-269) ProteinP01584 (Uniprot-TrEMBL)
Interleukin-1 family


ComplexR-HSA-449026 (Reactome)
Interleukin-1 family propeptidesComplexR-HSA-449039 (Reactome)
Interleukin-1 familyComplexR-HSA-449027 (Reactome)
Interleukin-1 familyComplexR-HSA-449063 (Reactome)
Myr82K-Myr83K-IL1A ProteinP01583 (Uniprot-TrEMBL)
NFKB1(1-433) ProteinP19838 (Uniprot-TrEMBL)
NFKB2(1-454) ProteinQ00653 (Uniprot-TrEMBL)
NFkB ComplexComplexR-HSA-177673 (Reactome)
RELA ProteinQ04206 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
CASP1(1-119)ArrowR-HSA-448678 (Reactome)
CASP1(1-404)R-HSA-448678 (Reactome)
CASP1(120-197):CASP1(317-404)ArrowR-HSA-448673 (Reactome)
CASP1(120-197):CASP1(317-404)R-HSA-448702 (Reactome)
CASP1(120-297)ArrowR-HSA-448678 (Reactome)
CASP1(120-297)R-HSA-448673 (Reactome)
CASP1(298-316)ArrowR-HSA-448678 (Reactome)
CASP1(317-404)ArrowR-HSA-448678 (Reactome)
CASP1(317-404)R-HSA-448673 (Reactome)
Caspase-1 tetramerArrowR-HSA-448702 (Reactome)
Caspase-1 tetramermim-catalysisR-HSA-448703 (Reactome)
Interleukin-1 family


ArrowR-HSA-448703 (Reactome)
Interleukin-1 family propeptidesR-HSA-448703 (Reactome)
Interleukin-1 familyArrowR-HSA-448703 (Reactome)
Interleukin-1 familyArrowR-HSA-449058 (Reactome)
Interleukin-1 familyR-HSA-449058 (Reactome)
NFkB ComplexArrowR-HSA-448703 (Reactome)
R-HSA-448673 (Reactome) The p10 and p20 subunits first dimerize, then two dimers associate to give the active tetramer.
R-HSA-448678 (Reactome) Caspase 1 is expressed as a precursor that is cleaved to generate the p10 and p20 subunits that subsequently form the active tetramer.
R-HSA-448702 (Reactome) Two p10/p20 dimers associate to form the active tetramer
R-HSA-448703 (Reactome) Pro-interleukin-1 beta (pro-IL1B) is the primary substrate of caspase-1. IL1B production and processing is stimulated when pathogen-associated molecular patterns (PAMPs) such as bacterial LPS are detected by cells of the innate immune system, and in response to pro-inflammatory cytokines such as TNF. Detection of PAMPs by Toll receptors leads to rapid IL1 transcription/translation and subsequent processing by caspase-1 in macrophages and monocytes. Processing is triggered by the activation of members of the NLR family and their associated inflammasome complexes. IL1B lacks a signal peptide to direct it to the Golgi for subsequent secretion, so the mode of secretion is uncertain. Once secreted, IL1B binds membrane-bound IL1 receptors, followed by recruitment of the IL1 receptor accessory protein to form a high affinity receptor complex. Ligand induced receptor activation induces the intracellular association of a number of cytosolic adapter proteins triggering intracellular signal transduction. This series of steps facilitates the induction of nuclear factor-kappa B (NFkB) and mitogen-activated protein kinase (MAPK) activity, leading to downstream transcription of additional inflammatory cytokines, including IL1B itself. A calpain-like potease has been reported to be important for the processing of pro- IL1A, but much less is known about how IL1A is released from cells and what specific roles it plays in biology.
R-HSA-449058 (Reactome) IL-1 Beta lacks signal sequences for compartmentation within the Golgi and classical secretory vesicles, so release of the mature form to extracellular compartments requires nonclassical mechanisms of secretion which are poorly understood. Three models with distinct mechanisms have been proposed to date (see Qu et al. 2007).
Personal tools