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Protein

Caspase-4

Gene

Casp4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Proinflammatory caspase (PubMed:8702803, PubMed:9038361, 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, as well as infection with Gram-negative bacteria (PubMed:22002608). 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:22002608, PubMed:26320999, PubMed:26375003). Plays a crucial role in the restriction of Salmonella typhimurium replication in colonic epithelial cells during infection. In later stages of the infection (>3 days post infection), LPS from cytosolic Salmonella triggers CASP4 activation, which ultimately results in the pyroptosis of the 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 (PubMed:25121752). Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (By similarity). Involved in cell death induced by endoplasmic reticulum stress (By similarity). Activated by direct binding to LPS without the need of an upstream sensor (PubMed:25119034). Does not directly process IL1B (PubMed:8702803, PubMed:9038361). During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation (PubMed:28314590).By similarity8 Publications

Caution

Catalytic activityi

Strict requirement for Asp at the P1 position and has a preferred cleavage sequence of (Ile/Leu/Val/Phe)-Gly-His-Asp-|-.By similarity

Enzyme regulationi

Activated by homooligomerization induced by direct binding to cytosolic LPS, in a TLR4-independent manner.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei206By similarity1
Active sitei254By similarity1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionHydrolase, Protease, Thiol protease
Biological processImmunity, Inflammatory response, Innate immunity, Necrosis

Enzyme and pathway databases

BRENDAi3.4.22.57 3474
3.4.22.64 3474

Protein family/group databases

MEROPSiC14.012

Names & Taxonomyi

Protein namesi
Recommended name:
Caspase-4 (EC:3.4.22.64By similarity)
Short name:
CASP-4
Alternative name(s):
Caspase-11
Short name:
CASP-11
Protease ICH-31 Publication
Cleaved into the following 2 chains:
Gene namesi
Name:Casp4
Synonyms:Casp11, Caspl, Ich3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 9

Organism-specific databases

MGIiMGI:107700 Casp4

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Endoplasmic reticulum, Inflammasome, Membrane, Mitochondrion, Secreted

Pathology & Biotechi

Disruption phenotypei

Mutant animals are largely resistant to LPS-induced lethal septic shock (PubMed:22002608, PubMed:26375259). However, they are susceptible to Burkholderia thailandensis infection, even at low bacterial doses (PubMed:26320999). During intestinal Salmonella Typhimurium infection, mutant animals display higher pathogen loads in their cecal tissues and lumen and lower levels of IL18 in cecal explants, associated with a significant reduction in cecal inflammation (PubMed:25121752). Bone-marrow-derived macrophages from knockout mice respond normally, in terms of IL1B secretion, to canonical inflammasome activators, such as ATP, monosodium urate, poly(dA:dT) double-stranded DNA, Francisella tularensis, flagellin or Pseudomonas aeruginosa, but fail to secrete IL1B in response to cholera enterotoxin subunit B. They also do not respond to live E. coli, C. rodentium and V. cholerae, with or without LPS priming (PubMed:22002608).4 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi19K → E: Severely attenuated LPS-binding, LPS-induced oligomerization and activation, and LPS-induced pyroptosis. 1 Publication1
Mutagenesisi38K → E: No effect on LPS-binding, LPS-induced oligomerization, and LPS-induced pyroptosis; when associated with M-40. 1 Publication1
Mutagenesisi40E → M: No effect on LPS-binding, LPS-induced oligomerization, and LPS-induced pyroptosis; when associated with E-38. 1 Publication1
Mutagenesisi53K → E: Complete loss of LPS-binding, LPS-induced oligomerization, and LPS-induced pyroptosis; when associated with E-54 and A-55. 1 Publication1
Mutagenesisi54R → E: Complete loss of LPS-binding, LPS-induced oligomerization, and LPS-induced pyroptosis; when associated with E-53 and A-55. 1 Publication1
Mutagenesisi55W → A: Complete loss of LPS-binding, LPS-induced oligomerization, and LPS-induced pyroptosis; when associated with E-54 and A-55. 1 Publication1
Mutagenesisi62K → E: Severely attenuated LPS-binding, LPS-induced oligomerization and activation, and LPS-induced pyroptosis; when associated with E-63 and E-64. 1 Publication1
Mutagenesisi63K → E: Severely attenuated LPS-binding, LPS-induced oligomerization and activation, and LPS-induced pyroptosis; when associated with E-62 and E-64. 1 Publication1
Mutagenesisi64K → E: Severely attenuated LPS-binding, LPS-induced oligomerization and activation, and LPS-induced pyroptosis; when associated with E-62 and E-63. 1 Publication1
Mutagenesisi254C → A: Loss of catalytic activity and of autocatalytic processing. Loss of LPS-induced pyroptosis. No effect on the interaction with LPS. 3 Publications1
Mutagenesisi254C → G: No cell death. 1

Chemistry databases

ChEMBLiCHEMBL1075276

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
PropeptideiPRO_00000046001 – 80Sequence analysisAdd BLAST80
ChainiPRO_000000460181 – 266Caspase-4 subunit p20Add BLAST186
PropeptideiPRO_0000004602267 – 285Sequence analysisAdd BLAST19
ChainiPRO_0000004603286 – 373Caspase-4 subunit p10Add BLAST88

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei83PhosphoserineBy similarity1

Post-translational modificationi

In response to activation signals, including cholera enterotoxin subunit B, infection by E. coli or S. typhimurium or endoplasmic reticulum stress, undergoes autoproteolytic cleavage.2 Publications

Keywords - PTMi

Phosphoprotein, Zymogen

Proteomic databases

MaxQBiP70343
PaxDbiP70343
PRIDEiP70343

PTM databases

PhosphoSitePlusiP70343

Miscellaneous databases

PMAP-CutDBiQ3TAF3

Expressioni

Tissue specificityi

Widely expressed, including in thymus, lung and spleen (at protein level). Very low levels, if any, in the brain.2 Publications

Inductioni

Up-regulated by LPS and E.coli (PubMed:8702803, PubMed:10986288, PubMed:22002608, PubMed:26375259). In LPS-induced lung inflammation, markedly up-regulated after 6 hours of treatment and decreases at 24 hours. The induction is dependent upon DDIT3/CHOP-mediated ER stress (at protein level) (PubMed:16670335). In the spleen and in bone marrow-derived macrophages, up-regulated by poly(I:C), a synthetic analog of double-stranded RNA (at protein level) (PubMed:26320999, PubMed:26375259). Also induced by IFNG and interferon-alpha. Up-regulated by R848, a TLR7 synthetic activator, and Pam3CysK4, a synthetic activator of TLR1/TLR2 (PubMed:26375259).6 Publications

Gene expression databases

BgeeiENSMUSG00000033538
CleanExiMM_CASP4
ExpressionAtlasiP70343 baseline and differential
GenevisibleiP70343 MM

Interactioni

Subunit structurei

Upon direct LPS-binding, forms large homooligomers, resulting in its activation. These oligomers are often referred to as 'non-canonical inflammasomes' (PubMed:25119034). Active as a heterotetramer consisting of two anti-parallel arranged heterodimers, each one formed by a small and a large subunit (By similarity). In its precursor form, interacts with TMEM214; this interaction is required for association with the endoplasmic reticulum membrane. Interacts with CASP1. Interacts with NOD2.By similarity1 Publication

GO - Molecular functioni

Protein-protein interaction databases

DIPiDIP-61776N
IntActiP70343 2 interactors.
STRINGi10090.ENSMUSP00000027012

Chemistry databases

BindingDBiP70343

Structurei

3D structure databases

ProteinModelPortaliP70343
SMRiP70343
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini1 – 91CARDPROSITE-ProRule annotationAdd BLAST91

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 59Required for LPS-binding1 PublicationAdd BLAST59

Domaini

The CARD domain mediates LPS recognition and homooligomerization.1 Publication

Sequence similaritiesi

Belongs to the peptidase C14A family.Curated

Phylogenomic databases

eggNOGiKOG3573 Eukaryota
ENOG410ZQIE LUCA
GeneTreeiENSGT00910000144131
HOGENOMiHOG000234399
HOVERGENiHBG076981
InParanoidiP70343
KOiK04394
OMAiFFNIDQI
OrthoDBiEOG091G07NO
TreeFamiTF102023

Family and domain databases

CDDicd00032 CASc, 1 hit
InterProiView protein in InterPro
IPR001315 CARD
IPR029030 Caspase-like_dom_sf
IPR033139 Caspase_cys_AS
IPR016129 Caspase_his_AS
IPR011029 DEATH-like_dom_sf
IPR002138 Pept_C14_p10
IPR001309 Pept_C14_p20
IPR015917 Pept_C14A
PfamiView protein in Pfam
PF00619 CARD, 1 hit
PRINTSiPR00376 IL1BCENZYME
SMARTiView protein in SMART
SM00114 CARD, 1 hit
SM00115 CASc, 1 hit
SUPFAMiSSF47986 SSF47986, 1 hit
SSF52129 SSF52129, 1 hit
PROSITEiView protein in PROSITE
PS50209 CARD, 1 hit
PS01122 CASPASE_CYS, 1 hit
PS01121 CASPASE_HIS, 1 hit
PS50207 CASPASE_P10, 1 hit
PS50208 CASPASE_P20, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P70343-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAENKHPDKP LKVLEQLGKE VLTEYLEKLV QSNVLKLKEE DKQKFNNAER
60 70 80 90 100
SDKRWVFVDA MKKKHSKVGE MLLQTFFSVD PGSHHGEANL EMEEPEESLN
110 120 130 140 150
TLKLCSPEEF TRLCREKTQE IYPIKEANGR TRKALIICNT EFKHLSLRYG
160 170 180 190 200
ANFDIIGMKG LLEDLGYDVV VKEELTAEGM ESEMKDFAAL SEHQTSDSTF
210 220 230 240 250
LVLMSHGTLH GICGTMHSEK TPDVLQYDTI YQIFNNCHCP GLRDKPKVII
260 270 280 290 300
VQACRGGNSG EMWIRESSKP QLCRGVDLPR NMEADAVKLS HVEKDFIAFY
310 320 330 340 350
STTPHHLSYR DKTGGSYFIT RLISCFRKHA CSCHLFDIFL KVQQSFEKAS
360 370
IHSQMPTIDR ATLTRYFYLF PGN
Length:373
Mass (Da):42,742
Last modified:July 27, 2011 - v2
Checksum:i110D7AA75E71C2B3
GO
Isoform 2 (identifier: P70343-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     88-118: ANLEMEEPEESLNTLKLCSPEEFTRLCREKT → DLPNKGGQWPYTKGSYHMQYRVQTSLTEVWG
     119-373: Missing.

Note: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. No experimental confirmation available.Curated
Show »
Length:118
Mass (Da):13,746
Checksum:i10393D4DF7045252
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti126E → K in AAH61255 (PubMed:15489334).Curated1
Sequence conflicti152N → K in AAB09469 (PubMed:8702803).Curated1

Polymorphismi

A variant of this gene has been observed in several 129 substrains, including 129/SvJ, 129S1/Sv, 129P3/J and 129S6/SvEvTac. This variant displays a 5-bp deletion encompassing the exon 7 splice acceptor junction. As a result, exon 7 is spliced out. Joining of exon 6 to exon 8 creates a frameshift after Pro-304 and a stop codon occurs after 5 aberrant amino acids. The mRNA may be the target of nonsense-mediated mRNA decay. It is detected only at low levels, while the corresponding protein is not detected at all in any of the 129 substrains tested.1 Publication

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_05818388 – 118ANLEM…CREKT → DLPNKGGQWPYTKGSYHMQY RVQTSLTEVWG in isoform 2. 1 PublicationAdd BLAST31
Alternative sequenceiVSP_058184119 – 373Missing in isoform 2. 1 PublicationAdd BLAST255

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U59463 mRNA Translation: AAB09469.1
Y13089 mRNA Translation: CAA73531.1
AB480706 mRNA Translation: BAH96541.1
AK151547 mRNA Translation: BAE30493.1
AK171877 mRNA Translation: BAE42715.1
AC141637 Genomic DNA No translation available.
CH466636 Genomic DNA Translation: EDL09318.1
BC061255 mRNA Translation: AAH61255.1
CCDSiCCDS22799.1 [P70343-1]
RefSeqiNP_031635.2, NM_007609.3 [P70343-1]
UniGeneiMm.1569

Genome annotation databases

EnsembliENSMUST00000027012; ENSMUSP00000027012; ENSMUSG00000033538 [P70343-1]
ENSMUST00000160064; ENSMUSP00000124249; ENSMUSG00000033538 [P70343-2]
GeneIDi12363
KEGGimmu:12363
UCSCiuc009obt.3 mouse [P70343-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiCASP4_MOUSE
AccessioniPrimary (citable) accession number: P70343
Secondary accession number(s): C6L648
, O08735, Q3TAF3, Q6P8H1
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: July 27, 2011
Last modified: April 25, 2018
This is version 159 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome