UniProt functional annotation for Q3UP24



	UniProt functional annotation for Q3UP24

UniProt code: Q3UP24.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Key component of inflammasomes that indirectly senses specific proteins from pathogenic bacteria and fungi and responds by assembling an inflammasome complex that promotes caspase-1 activation, cytokine production and macrophage pyroptosis. The NLRC4 inflammasome is activated as part of the innate immune response to a range of intracellular bacteria. It senses pathogenic proteins of the type III secretion system (T3SS) and type IV secretion system (T4SS) such as flagellin and PrgJ-like rod proteins via the Naip proteins (Naip1, Naip2 or Naip5): specific Naip proteins recognize and bind pathogenic proteins, driving assembly and activation of the NLRC4 inflammasome. The NLRC4 inflammasome senses Gram-negative bacteria such as L.pneumophila and P.aeruginosa, enteric pathogens S.typhimurium (Salmonella) and S.flexneri and fungal pathogen C.albicans. In intestine, the NLRC4 inflammasome is able to discriminate between commensal and pathogenic bacteria and specifically drives production of interleukin-1 beta (IL1B) in response to infection by Salmonella or P.aeruginosa. In case of L.pneumophila infection the inflammasome acts by activating caspase-7. {ECO:0000269|PubMed:15190255, ECO:0000269|PubMed:16648852, ECO:0000269|PubMed:16648853, ECO:0000269|PubMed:18070936, ECO:0000269|PubMed:19343209, ECO:0000269|PubMed:20133635, ECO:0000269|PubMed:20603313, ECO:0000269|PubMed:21874021, ECO:0000269|PubMed:21918512, ECO:0000269|PubMed:22174673, ECO:0000269|PubMed:22231517, ECO:0000269|PubMed:22484733, ECO:0000269|PubMed:22547706, ECO:0000269|PubMed:22885697, ECO:0000269|PubMed:29146805, ECO:0000269|PubMed:29182158}.

Subunit: Homooligomer; homooligomerizes following activation of Naip proteins by pathogenic proteins such as S.typhimurium (Salmonella) flagellin or PrgJ (PubMed:23765277, PubMed:26449474, PubMed:26585513, PubMed:29146805). Component of the NLRC4 inflammasome, at least composed of NLRC4, caspase-1 (CASP1) and some NAIP protein (Naip, Naip2 or Naip5) (PubMed:21874021, PubMed:21918512, PubMed:26585513). Interacts with Naip5 and Naip6; following Naip5 and Naip6 engagement by Salmonella flagellin (PubMed:21874021, PubMed:21918512, PubMed:29182158, PubMed:29146805). Interacts with Naip2; following Naip2 engagement by Salmonella PrgJ (PubMed:21874021, PubMed:21918512, PubMed:26449474). The inflammasome is a huge complex that contains multiple copies of NLRC4 and a single Naip protein chain (PubMed:26449474, PubMed:29146805). Some NLRC4 inflammasomes contain PYCARD/ASC, while some others directly contact and activate CASP1 (PubMed:21147462). Interacts with EIF2AK2/PKR (By similarity). {ECO:0000250|UniProtKB:Q9NPP4, ECO:0000269|PubMed:21147462, ECO:0000269|PubMed:21874021, ECO:0000269|PubMed:21918512, ECO:0000269|PubMed:23765277, ECO:0000269|PubMed:26449474, ECO:0000269|PubMed:26585513, ECO:0000269|PubMed:29146805}.

Subcellular location: Cytoplasm, cytosol {ECO:0000269|PubMed:22885697}. Inflammasome {ECO:0000269|PubMed:21874021, ECO:0000269|PubMed:21918512, ECO:0000269|PubMed:26585513}.

Tissue specificity: Expressed by intestinal mononuclear phagocytes. {ECO:0000269|PubMed:22484733}.

Domain: In an autoinhibited form the C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. An ADP- mediated interaction between the NBD and the WHD also contributes to the autoinhibition (PubMed:23765277). {ECO:0000269|PubMed:23765277}.

Ptm: Phosphorylated at Ser-533 following infection of macrophages with S.typhimurium (Salmonella). Phosphorylation is essential for NLRC4 inflammasome function to promote caspase-1 activation and pyroptosis. PRKCD phosphorylates Ser-533 in vitro. {ECO:0000269|PubMed:22885697, ECO:0000269|PubMed:23765277}.

Disruption phenotype: Mice show defects in inflammasome function in response to S.typhimurium (Salmonella) infection. Differences are however observed depending on the strain background: in a C57BL/6J strain background, no striking differences are observed compared to wild-type mice following Salmonella infection. While in a BALB/c strain background, mice are highly susceptible to orogastric but not intraperitoneal infection with Salmonella: enhanced lethality is preceded by impaired expression of endothelial adhesion molecules, lower neutrophil recruitment and poor intestinal pathogen clearance. {ECO:0000269|PubMed:15190255, ECO:0000269|PubMed:16717117, ECO:0000269|PubMed:22484733}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Key component of inflammasomes that indirectly senses specific proteins from pathogenic bacteria and fungi and responds by assembling an inflammasome complex that promotes caspase-1 activation, cytokine production and macrophage pyroptosis. The NLRC4 inflammasome is activated as part of the innate immune response to a range of intracellular bacteria. It senses pathogenic proteins of the type III secretion system (T3SS) and type IV secretion system (T4SS) such as flagellin and PrgJ-like rod proteins via the Naip proteins (Naip1, Naip2 or Naip5): specific Naip proteins recognize and bind pathogenic proteins, driving assembly and activation of the NLRC4 inflammasome. The NLRC4 inflammasome senses Gram-negative bacteria such as L.pneumophila and P.aeruginosa, enteric pathogens S.typhimurium (Salmonella) and S.flexneri and fungal pathogen C.albicans. In intestine, the NLRC4 inflammasome is able to discriminate between commensal and pathogenic bacteria and specifically drives production of interleukin-1 beta (IL1B) in response to infection by Salmonella or P.aeruginosa. In case of L.pneumophila infection the inflammasome acts by activating caspase-7. {ECO:0000269\|PubMed:15190255, ECO:0000269\|PubMed:16648852, ECO:0000269\|PubMed:16648853, ECO:0000269\|PubMed:18070936, ECO:0000269\|PubMed:19343209, ECO:0000269\|PubMed:20133635, ECO:0000269\|PubMed:20603313, ECO:0000269\|PubMed:21874021, ECO:0000269\|PubMed:21918512, ECO:0000269\|PubMed:22174673, ECO:0000269\|PubMed:22231517, ECO:0000269\|PubMed:22484733, ECO:0000269\|PubMed:22547706, ECO:0000269\|PubMed:22885697, ECO:0000269\|PubMed:29146805, ECO:0000269\|PubMed:29182158}.


Subunit:		Homooligomer; homooligomerizes following activation of Naip proteins by pathogenic proteins such as S.typhimurium (Salmonella) flagellin or PrgJ (PubMed:23765277, PubMed:26449474, PubMed:26585513, PubMed:29146805). Component of the NLRC4 inflammasome, at least composed of NLRC4, caspase-1 (CASP1) and some NAIP protein (Naip, Naip2 or Naip5) (PubMed:21874021, PubMed:21918512, PubMed:26585513). Interacts with Naip5 and Naip6; following Naip5 and Naip6 engagement by Salmonella flagellin (PubMed:21874021, PubMed:21918512, PubMed:29182158, PubMed:29146805). Interacts with Naip2; following Naip2 engagement by Salmonella PrgJ (PubMed:21874021, PubMed:21918512, PubMed:26449474). The inflammasome is a huge complex that contains multiple copies of NLRC4 and a single Naip protein chain (PubMed:26449474, PubMed:29146805). Some NLRC4 inflammasomes contain PYCARD/ASC, while some others directly contact and activate CASP1 (PubMed:21147462). Interacts with EIF2AK2/PKR (By similarity). {ECO:0000250\|UniProtKB:Q9NPP4, ECO:0000269\|PubMed:21147462, ECO:0000269\|PubMed:21874021, ECO:0000269\|PubMed:21918512, ECO:0000269\|PubMed:23765277, ECO:0000269\|PubMed:26449474, ECO:0000269\|PubMed:26585513, ECO:0000269\|PubMed:29146805}.
Subcellular location:		Cytoplasm, cytosol {ECO:0000269\|PubMed:22885697}. Inflammasome {ECO:0000269\|PubMed:21874021, ECO:0000269\|PubMed:21918512, ECO:0000269\|PubMed:26585513}.
Tissue specificity:		Expressed by intestinal mononuclear phagocytes. {ECO:0000269\|PubMed:22484733}.
Domain:		In an autoinhibited form the C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. An ADP- mediated interaction between the NBD and the WHD also contributes to the autoinhibition (PubMed:23765277). {ECO:0000269\|PubMed:23765277}.
Ptm:		Phosphorylated at Ser-533 following infection of macrophages with S.typhimurium (Salmonella). Phosphorylation is essential for NLRC4 inflammasome function to promote caspase-1 activation and pyroptosis. PRKCD phosphorylates Ser-533 in vitro. {ECO:0000269\|PubMed:22885697, ECO:0000269\|PubMed:23765277}.
Disruption phenotype:		Mice show defects in inflammasome function in response to S.typhimurium (Salmonella) infection. Differences are however observed depending on the strain background: in a C57BL/6J strain background, no striking differences are observed compared to wild-type mice following Salmonella infection. While in a BALB/c strain background, mice are highly susceptible to orogastric but not intraperitoneal infection with Salmonella: enhanced lethality is preceded by impaired expression of endothelial adhesion molecules, lower neutrophil recruitment and poor intestinal pathogen clearance. {ECO:0000269\|PubMed:15190255, ECO:0000269\|PubMed:16717117, ECO:0000269\|PubMed:22484733}.