Interleukin-1 processing (Homo sapiens)

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12-45666nucleoplasmcytosolIL18 IL1B(1-116) CASP1(1-119)Interleukin-1 familypropeptidesCaspase-1 tetramerIL18 RELA Interleukin-1 familyIL18(1-193) CTSGCASP1(120-297)NFKB1(1-433) IL1A(1-112) NFkB ComplexCASP1(120-297) CASP1(317-404) Interleukin-1 familyIL1B 2xMyri-IL1A IL1B(1-269) Myr82K-Myr83K-IL1A IL18(1-36) CASP1(120-197):CASP1(317-404)IL1A(1-271) CASP1(1-404)CASP1(317-404)CASP1(317-404) CASP1(298-316)CASP1(120-297) IL1B(117-269) NFKB2(1-454) Interleukin-1 familyN-terminalpropeptides7


Description

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 These proposals superceded previous models in which non-specific release due to cell lysis and passage through a plasma membrane pore were considered.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.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 448706
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Ray, KP

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Bibliography

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  1. Brough D, Rothwell NJ.; ''Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death.''; PubMed Europe PMC Scholia
  2. 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 Scholia
  3. 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 Scholia
  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 Scholia
  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 Scholia
  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 Scholia
  7. Campbell EJ, Silverman EK, Campbell MA.; ''Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114673view16:14, 25 January 2021ReactomeTeamReactome version 75
113120view11:18, 2 November 2020ReactomeTeamReactome version 74
112354view15:28, 9 October 2020ReactomeTeamReactome version 73
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

DataNodes

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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)
CTSGProteinP08311 (Uniprot-TrEMBL) After secretion Cathepsin G is extracellular and associated with the plasma membrane.
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

N-terminal

propeptides
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

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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)
CTSGmim-catalysisR-HSA-448678 (Reactome)
Caspase-1 tetramerArrowR-HSA-448702 (Reactome)
Caspase-1 tetramermim-catalysisR-HSA-448703 (Reactome)
Interleukin-1 family

N-terminal

propeptides
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) Interleukin-1β (IL-1β) 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 (Eder C 2009; Piccioli P & Rubartelli A 2013). Several secretory pathways were proposed involving secretory lysosomes, exosomes, microvesicles, and autophagic vesicles, possibly through a mechanism similar to chaperone-mediated autophagy (CMA) (Andrei C et al. 2004; Ward JR et al. 2010; MacKenzie A et al. 2001; Gudipaty L et al. 2003; Qu Y et al. 2007; Iula L et al. 2018: reviewed by Eder C 2009; Piccioli P & Rubartelli A 2013; Claude-Taupin A et al. 2018). Further, the route of IL-1β secretion was found to be dependent on the type and strength of the inflammatory stimuli (Semino C et al. 2018; Sitia R & Rubartelli A 2018). Thus, in primary human monocytes small trauma or low pathogen load (LPS) activated a pathway involving secretory lysosomes that allows slow release of IL-1β, followed by apoptotic cell death that switches off the inflammatory response (Semino C et al. 2018). Differently, a stronger stimulus (LRZ) resulted in gasdermin D (GSDMD) cleavage with generation of the N-terminal domain that assembles in N-rings with formation of pores through which IL-1β can be externalized: this pathway of secretion is followed by pyroptosis, with membrane ruptures through which DAMPs can leave cells, further amplifying the inflammatory response (Semino C et al. 2018).
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