Caspase-4

Details

Name

Caspase-4

Synonyms

• 3.4.22.57
• CASP-4
• ICE and Ced-3 homolog 2
• ICE(rel)-II
• ICH-2
• ICH2
• Mih1
• Protease TX

Gene Name

CASP4

UniProtKB Entry

P49662Swiss-Prot

Organism

Humans

NCBI Taxonomy ID

9606

Amino acid sequence

>lcl|BSEQ0052467|Caspase-4
MAEGNHRKKPLKVLESLGKDFLTGVLDNLVEQNVLNWKEEEKKKYYDAKTEDKVRVMADS
MQEKQRMAGQMLLQTFFNIDQISPNKKAHPNMEAGPPESGESTDALKLCPHEEFLRLCKE
RAEEIYPIKERNNRTRLALIICNTEFDHLPPRNGADFDITGMKELLEGLDYSVDVEENLT
ARDMESALRAFATRPEHKSSDSTFLVLMSHGILEGICGTVHDEKKPDVLLYDTIFQIFNN
RNCLSLKDKPKVIIVQACRGANRGELWVRDSPASLEVASSQSSENLEEDAVYKTHVEKDF
IAFCSSTPHNVSWRDSTMGSIFITQLITCFQKYSWCCHLEEVFRKVQQSFETPRAKAQMP
TIERLSMTRYFYLFPGN

Number of residues

377

Molecular Weight

43261.87

Theoretical pI

Not Available

GO Classification

Functions

lipid binding / lipopolysaccharide binding

Processes

defense response to bacterium / defense response to Gram-positive bacterium / non-canonical inflammasome complex assembly / positive regulation of inflammatory response / positive regulation of interleukin-18-mediated signaling pathway / positive regulation of neuron apoptotic process / protein autoprocessing / protein maturation / pyroptosis

Components

NLRP1 inflammasome complex / non-canonical inflammasome complex

General Function

Inflammatory caspase that acts as the effector of the non-canonical inflammasome by mediating lipopolysaccharide (LPS)-induced pyroptosis (PubMed:25119034, PubMed:26375003, PubMed:32109412, PubMed:34671164, PubMed:37001519, PubMed:37993712, PubMed:37993714). Also indirectly activates the NLRP3 and NLRP6 inflammasomes (PubMed:23516580, PubMed:26375003, PubMed:32109412, PubMed:7797510). Acts as a thiol protease that cleaves a tetrapeptide after an Asp residue at position P1: catalyzes cleavage of CGAS, GSDMD and IL18 (PubMed:15326478, PubMed:23516580, PubMed:26375003, PubMed:28314590, PubMed:32109412, PubMed:37993712, PubMed:37993714, PubMed:7797510). Effector of the non-canonical inflammasome independently of NLRP3 inflammasome and CASP1: the non-canonical inflammasome promotes pyroptosis through GSDMD cleavage without involving secretion of cytokine IL1B (PubMed:25119034, PubMed:25121752, PubMed:26375003, PubMed:31268602, PubMed:32109412, PubMed:37993712, PubMed:37993714). In the non-canonical inflammasome, CASP4 is activated by direct binding to the lipid A moiety of LPS without the need of an upstream sensor (PubMed:25119034, PubMed:25121752, PubMed:29520027, PubMed:32510692, PubMed:32581219, PubMed:37993712). LPS-binding promotes CASP4 activation and CASP4-mediated cleavage of GSDMD and IL18, followed by IL18 secretion through the GSDMD pore, pyroptosis of infected cells and their extrusion into the gut lumen (PubMed:25119034, PubMed:25121752, PubMed:37993712, PubMed:37993714). Also indirectly promotes secretion of mature cytokines (IL1A and HMGB1) downstream of GSDMD-mediated pyroptosis via activation of the NLRP3 and NLRP6 inflammasomes (PubMed:26375003, PubMed:32109412). Involved in NLRP3-dependent CASP1 activation and IL1B secretion in response to non-canonical activators, such as UVB radiation or cholera enterotoxin (PubMed:22246630, PubMed:23516580, PubMed:24879791, PubMed:25964352, PubMed:26173988, PubMed:26174085, PubMed:26508369). Involved in NLRP6 inflammasome-dependent activation in response to lipoteichoic acid (LTA), a cell-wall component of Gram-positive bacteria, which leads to CASP1 activation and IL1B secretion (PubMed:33377178). Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (PubMed:26508369). The non-canonical inflammasome is required for innate immunity to cytosolic, but not vacuolar, bacteria (By similarity). Plays a crucial role in the restriction of S.typhimurium replication in colonic epithelial cells during infection (PubMed:25121752, PubMed:25964352). Activation of the non-canonical inflammasome in brain endothelial cells can lead to excessive pyroptosis, leading to blood-brain barrier breakdown (By similarity). Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation (PubMed:25121752, PubMed:25964352, PubMed:26375003). May also act as an activator of adaptive immunity in dendritic cells, following activation by oxidized phospholipid 1-palmitoyl-2-arachidonoyl- sn-glycero-3-phosphorylcholine, an oxidized phospholipid (oxPAPC) (By similarity). Involved in cell death induced by endoplasmic reticulum stress and by treatment with cytotoxic APP peptides found in Alzheimer's patient brains (PubMed:15123740, PubMed:22246630, PubMed:23661706). Cleavage of GSDMD is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP4 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32109412). Catalyzes cleavage and maturation of IL18; IL18 processing also depends of the exosite interface on CASP4 (PubMed:15326478, PubMed:37993712, PubMed:37993714). In contrast, it does not directly process IL1B (PubMed:7743998, PubMed:7797510, PubMed:7797592). During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation (PubMed:28314590)

Specific Function

Card domain binding

Pfam Domain Function

• CARD (PF00619)
• Peptidase_C14 (PF00656)

Signal Regions

Not Available

Transmembrane Regions

Not Available

Cellular Location

Cytoplasm, cytosol

Gene sequence

>lcl|BSEQ0052468|Caspase-4 (CASP4)
ATGGCAGAAGGCAACCACAGAAAAAAGCCACTTAAGGTGTTGGAATCCCTGGGCAAAGAT
TTCCTCACTGGTGTTTTGGATAACTTGGTGGAACAAAATGTACTGAACTGGAAGGAAGAG
GAAAAAAAGAAATATTACGATGCTAAAACTGAAGACAAAGTTCGGGTCATGGCAGACTCT
ATGCAAGAGAAGCAACGTATGGCAGGACAAATGCTTCTTCAAACCTTTTTTAACATAGAC
CAAATATCCCCCAATAAAAAAGCTCATCCGAATATGGAGGCTGGACCACCTGAGTCAGGA
GAATCTACAGATGCCCTCAAGCTTTGTCCTCATGAAGAATTCCTGAGACTATGTAAAGAA
AGAGCTGAAGAGATCTATCCAATAAAGGAGAGAAACAACCGCACACGCCTGGCTCTCATC
ATATGCAATACAGAGTTTGACCATCTGCCTCCGAGGAATGGAGCTGACTTTGACATCACA
GGGATGAAGGAGCTACTTGAGGGTCTGGACTATAGTGTAGATGTAGAAGAGAATCTGACA
GCCAGGGATATGGAGTCAGCGCTGAGGGCATTTGCTACCAGACCAGAGCACAAGTCCTCT
GACAGCACATTCTTGGTACTCATGTCTCATGGCATCCTGGAGGGAATCTGCGGAACTGTG
CATGATGAGAAAAAACCAGATGTGCTGCTTTATGACACCATCTTCCAGATATTCAACAAC
CGCAACTGCCTCAGTCTGAAGGACAAACCCAAGGTCATCATTGTCCAGGCCTGCAGAGGT
GCAAACCGTGGGGAACTGTGGGTCAGAGACTCTCCAGCATCCTTGGAAGTGGCCTCTTCA
CAGTCATCTGAGAACCTAGAGGAAGATGCTGTTTACAAGACCCACGTGGAGAAGGACTTC
ATTGCTTTCTGCTCTTCAACGCCACACAACGTGTCCTGGAGAGACAGCACAATGGGCTCT
ATCTTCATCACACAACTCATCACATGCTTCCAGAAATATTCTTGGTGCTGCCACCTAGAG
GAAGTATTTCGGAAGGTACAGCAATCATTTGAAACTCCAAGGGCCAAAGCTCAAATGCCC
ACCATAGAACGACTGTCCATGACAAGATATTTCTACCTCTTTCCTGGCAATTGA

Chromosome Location

11

Locus

11q22.3

External Identifiers

Resource	Link
UniProtKB ID	P49662
UniProtKB Entry Name	CASP4_HUMAN
GeneCard ID	CASP4
HGNC ID	HGNC:1505
PDB ID(s)	6KMZ, 6NRY, 7WR0, 7WR1, 7WR4, 7WR5, 7WR6, 8J6K, 8SPB
KEGG ID	hsa:837
IUPHAR/Guide To Pharmacology ID	1620
NCBI Gene ID	837

General References

1. 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. [Article]
2. 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. [Article]
3. 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. [Article]
4. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [Article]
5. Taylor TD, Noguchi H, Totoki Y, Toyoda A, Kuroki Y, Dewar K, Lloyd C, Itoh T, Takeda T, Kim DW, She X, Barlow KF, Bloom T, Bruford E, Chang JL, Cuomo CA, Eichler E, FitzGerald MG, Jaffe DB, LaButti K, Nicol R, Park HS, Seaman C, Sougnez C, Yang X, Zimmer AR, Zody MC, Birren BW, Nusbaum C, Fujiyama A, Hattori M, Rogers J, Lander ES, Sakaki Y: Human chromosome 11 DNA sequence and analysis including novel gene identification. Nature. 2006 Mar 23;440(7083):497-500. [Article]
6. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
7. Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Bocher M, Blocker H, Bauersachs S, Blum H, Lauber J, Dusterhoft A, Beyer A, Kohrer K, Strack N, Mewes HW, Ottenwalder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A: Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs. Genome Res. 2001 Mar;11(3):422-35. [Article]
8. Lin XY, Choi MS, Porter AG: Expression analysis of the human caspase-1 subfamily reveals specific regulation of the CASP5 gene by lipopolysaccharide and interferon-gamma. J Biol Chem. 2000 Dec 22;275(51):39920-6. doi: 10.1074/jbc.M007255200. [Article]
9. 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. Epub 2004 May 3. [Article]
10. Eckhart L, Kittel C, Gawlas S, Gruber F, Mildner M, Jilma B, Tschachler E: Identification of a novel exon encoding the amino-terminus of the predominant caspase-5 variants. Biochem Biophys Res Commun. 2006 Sep 22;348(2):682-8. Epub 2006 Jul 28. [Article]
11. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP: A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7. doi: 10.1073/pnas.0805139105. Epub 2008 Jul 31. [Article]
12. Hsu LC, Ali SR, McGillivray S, Tseng PH, Mariathasan S, Humke EW, Eckmann L, Powell JJ, Nizet V, Dixit VM, Karin M: A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7803-8. doi: 10.1073/pnas.0802726105. Epub 2008 May 29. [Article]
13. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal. 2010 Jan 12;3(104):ra3. doi: 10.1126/scisignal.2000475. [Article]
14. 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. [Article]
15. Van Damme P, Lasa M, Polevoda B, Gazquez C, Elosegui-Artola A, Kim DS, De Juan-Pardo E, Demeyer K, Hole K, Larrea E, Timmerman E, Prieto J, Arnesen T, Sherman F, Gevaert K, Aldabe R: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12449-54. doi: 10.1073/pnas.1210303109. Epub 2012 Jul 18. [Article]
16. 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. [Article]
17. 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. [Article]
18. 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. [Article]
19. 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. [Article]
20. 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. [Article]
21. 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. [Article]
22. 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. [Article]
23. 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. [Article]
24. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F: Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015 Oct 29;526(7575):660-5. doi: 10.1038/nature15514. Epub 2015 Sep 16. [Article]
25. Yang HJ, Wang M, Wang L, Cheng BF, Lin XY, Feng ZW: NF-kappaB regulates caspase-4 expression and sensitizes neuroblastoma cells to Fas-induced apoptosis. PLoS One. 2015 Feb 19;10(2):e0117953. doi: 10.1371/journal.pone.0117953. eCollection 2015. [Article]
26. 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. [Article]
27. 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. [Article]
28. Choi YJ, Kim S, Choi Y, Nielsen TB, Yan J, Lu A, Ruan J, Lee HR, Wu H, Spellberg B, Jung JU: SERPINB1-mediated checkpoint of inflammatory caspase activation. Nat Immunol. 2019 Mar;20(3):276-287. doi: 10.1038/s41590-018-0303-z. Epub 2019 Jan 28. [Article]

Associated Data

Bio-Entities

Bio-Entity	Type
Caspase-4 (Humans)	protein primary

Drug Relations

Drug	Drug group	Pharmacological action?	Type	Actions	Details
Incadronic acid	experimental	unknown	target	activator	Details