NLRC5
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NLRC5, short for NOD-like receptor family CARD domain containing 5, is an intracellular protein that plays a role in the immune system. NLRC5 is a pattern recognition receptor implicated in innate immunity to viruses potentially by regulating interferon activity.[1][2][3] It also acts as an innate immune sensor to drive inflammatory cell death, PANoptosis.[4][5] In humans, the NLRC5 protein is encoded by the NLRC5 gene.[6] It has also been called NOD27, NOD4, and CLR16.1.
Structure
[edit | edit source]Structurally, NLRC5 has a putative caspase recruitment domain (CARD), followed by a NACHT domain, and a C-terminal leucine-rich repeat (LRR) region.
Function
[edit | edit source]Through its structural features, NLRC5 acts as a key regulator of Major Histocompatibility Class I (MHCI) molecule expression,[7] playing a significant role in the adaptive immune system. This aspect of NLRC5 function was further investigated with the help of Nlrc5-deficient mice, which showed reduced MHCI expression in lymphocytes (particularly T, NK and NKT lymphocytes).[8] In lymphocytes, NLRC5 localizes to the nucleus and drives MHCI gene expression by occupying H-2D and H-2K gene promoters.[8]
NLRC5 also functions as an innate immune sensor that, upon NAD+ depletion, forms a PANoptosome, driving PANoptosis and inflammation.[4][5] PANoptosis is a prominent innate immune, inflammatory, and lytic cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting protein kinases (RIPKs) through PANoptosomes. PANoptosomes are multi-protein complexes assembled by germline-encoded pattern-recognition receptor(s) (PRRs) (innate immune sensor(s)) in response to pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, cytokines, and homeostatic changes during infections, inflammatory conditions, and cancer.[9][10] NLRC5 forms a PANoptosome complex with other NLRs, including NLRP12 and NLRP3, in response to NAD+ depletion, driving PANoptosis via caspase-8 and RIPK3. Deletion of Nlrc5 protects mice from lethality in hemolytic, hemophagocytic lymphohistiocytosis, and colitis models.[4][5]
References
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