7wr1

Structural highlights

Function

CASP4_HUMAN Inflammatory caspase (PubMed:7797510, PubMed:23516580, PubMed:25119034). Essential effector of NLRP3 inflammasome-dependent CASP1 activation and IL1B and IL18 secretion in response to non-canonical activators, such as UVB radiation, cholera enterotoxin subunit B and cytosolic LPS (PubMed:22246630, PubMed:26174085, PubMed:26173988, PubMed:26508369, PubMed:25964352). Independently of NLRP3 inflammasome and CASP1, promotes pyroptosis, through GSDMD cleavage and activation, and IL1A, IL18 and HMGB1 release in response to non-canonical inflammasome activators (PubMed:24879791, PubMed:25964352). Plays a crucial role in the restriction of Salmonella typhimurium replication in colonic epithelial cells during infection (PubMed:25121752). In later stages of the infection, LPS from cytosolic Salmonella triggers CASP4 activation, which ultimately results in pyroptosis of infected cells and their extrusion into the gut lumen, as well as in IL18 secretion. Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation. Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (PubMed:26508369). Involved in cell death induced by endoplasmic reticulum stress and by treatment with cytotoxic APP peptides found Alzheimer's patient brains (PubMed:15123740, PubMed:22246630, PubMed:23661706). Activated by direct binding to LPS without the need of an upstream sensor (PubMed:25119034). Does not directly process IL1B (PubMed:7743998, PubMed:7797592, PubMed:7797510). During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation (PubMed:28314590).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]}

References

1. ↑ Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K, Tsujimoto Y, Tohyama M. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol. 2004 May 10;165(3):347-56. doi: 10.1083/jcb.200310015. Epub 2004 May, 3. PMID:15123740 doi:http://dx.doi.org/10.1083/jcb.200310015
2. ↑ Sollberger G, Strittmatter GE, Kistowska M, French LE, Beer HD. Caspase-4 is required for activation of inflammasomes. J Immunol. 2012 Feb 15;188(4):1992-2000. doi: 10.4049/jimmunol.1101620. Epub 2012, Jan 13. PMID:22246630 doi:http://dx.doi.org/10.4049/jimmunol.1101620
3. ↑ Blasche S, Mortl M, Steuber H, Siszler G, Nisa S, Schwarz F, Lavrik I, Gronewold TM, Maskos K, Donnenberg MS, Ullmann D, Uetz P, Kogl M. The E. coli effector protein NleF is a caspase inhibitor. PLoS One. 2013;8(3):e58937. doi: 10.1371/journal.pone.0058937. Epub 2013 Mar 14. PMID:23516580 doi:http://dx.doi.org/10.1371/journal.pone.0058937
4. ↑ Li C, Wei J, Li Y, He X, Zhou Q, Yan J, Zhang J, Liu Y, Liu Y, Shu HB. Transmembrane Protein 214 (TMEM214) mediates endoplasmic reticulum stress-induced caspase 4 enzyme activation and apoptosis. J Biol Chem. 2013 Jun 14;288(24):17908-17. doi: 10.1074/jbc.M113.458836. Epub, 2013 May 9. PMID:23661706 doi:http://dx.doi.org/10.1074/jbc.M113.458836
5. ↑ Kajiwara Y, Schiff T, Voloudakis G, Gama Sosa MA, Elder G, Bozdagi O, Buxbaum JD. A critical role for human caspase-4 in endotoxin sensitivity. J Immunol. 2014 Jul 1;193(1):335-43. doi: 10.4049/jimmunol.1303424. Epub 2014 May, 30. PMID:24879791 doi:http://dx.doi.org/10.4049/jimmunol.1303424
6. ↑ Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, Hu L, Shao F. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature. 2014 Oct 9;514(7521):187-92. doi: 10.1038/nature13683. Epub 2014 Aug 6. PMID:25119034 doi:http://dx.doi.org/10.1038/nature13683
7. ↑ Knodler LA, Crowley SM, Sham HP, Yang H, Wrande M, Ma C, Ernst RK, Steele-Mortimer O, Celli J, Vallance BA. Noncanonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens. Cell Host Microbe. 2014 Aug 13;16(2):249-256. doi: 10.1016/j.chom.2014.07.002. PMID:25121752 doi:http://dx.doi.org/10.1016/j.chom.2014.07.002
8. ↑ Casson CN, Yu J, Reyes VM, Taschuk FO, Yadav A, Copenhaver AM, Nguyen HT, Collman RG, Shin S. Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens. Proc Natl Acad Sci U S A. 2015 May 26;112(21):6688-93. doi:, 10.1073/pnas.1421699112. Epub 2015 May 11. PMID:25964352 doi:http://dx.doi.org/10.1073/pnas.1421699112
9. ↑ Baker PJ, Boucher D, Bierschenk D, Tebartz C, Whitney PG, D'Silva DB, Tanzer MC, Monteleone M, Robertson AA, Cooper MA, Alvarez-Diaz S, Herold MJ, Bedoui S, Schroder K, Masters SL. NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5. Eur J Immunol. 2015 Oct;45(10):2918-26. doi: 10.1002/eji.201545655. Epub 2015 Aug, 24. PMID:26173988 doi:http://dx.doi.org/10.1002/eji.201545655
10. ↑ Schmid-Burgk JL, Gaidt MM, Schmidt T, Ebert TS, Bartok E, Hornung V. Caspase-4 mediates non-canonical activation of the NLRP3 inflammasome in human myeloid cells. Eur J Immunol. 2015 Oct;45(10):2911-7. doi: 10.1002/eji.201545523. Epub 2015 Aug , 6. PMID:26174085 doi:http://dx.doi.org/10.1002/eji.201545523
11. ↑ Vigano E, Diamond CE, Spreafico R, Balachander A, Sobota RM, Mortellaro A. Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes. Nat Commun. 2015 Oct 28;6:8761. doi: 10.1038/ncomms9761. PMID:26508369 doi:http://dx.doi.org/10.1038/ncomms9761
12. ↑ Wang Y, Ning X, Gao P, Wu S, Sha M, Lv M, Zhou X, Gao J, Fang R, Meng G, Su X, Jiang Z. Inflammasome Activation Triggers Caspase-1-Mediated Cleavage of cGAS to Regulate Responses to DNA Virus Infection. Immunity. 2017 Mar 21;46(3):393-404. doi: 10.1016/j.immuni.2017.02.011. Epub 2017, Mar 14. PMID:28314590 doi:http://dx.doi.org/10.1016/j.immuni.2017.02.011
13. ↑ Faucheu C, Diu A, Chan AW, Blanchet AM, Miossec C, Herve F, Collard-Dutilleul V, Gu Y, Aldape RA, Lippke JA, et al.. A novel human protease similar to the interleukin-1 beta converting enzyme induces apoptosis in transfected cells. EMBO J. 1995 May 1;14(9):1914-22. PMID:7743998
14. ↑ Kamens J, Paskind M, Hugunin M, Talanian RV, Allen H, Banach D, Bump N, Hackett M, Johnston CG, Li P, et al.. Identification and characterization of ICH-2, a novel member of the interleukin-1 beta-converting enzyme family of cysteine proteases. J Biol Chem. 1995 Jun 23;270(25):15250-6. doi: 10.1074/jbc.270.25.15250. PMID:7797510 doi:http://dx.doi.org/10.1074/jbc.270.25.15250
15. ↑ Munday NA, Vaillancourt JP, Ali A, Casano FJ, Miller DK, Molineaux SM, Yamin TT, Yu VL, Nicholson DW. Molecular cloning and pro-apoptotic activity of ICErelII and ICErelIII, members of the ICE/CED-3 family of cysteine proteases. J Biol Chem. 1995 Jun 30;270(26):15870-6. PMID:7797592