NLRC5
{{Short description|Protein-coding gene in the species Homo sapiens}}
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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.{{cite journal | vauthors = Neerincx A, Lautz K, Menning M, Kremmer E, Zigrino P, Hösel M, Büning H, Schwarzenbacher R, Kufer TA | title = A role for the human nucleotide-binding domain, leucine-rich repeat-containing family member NLRC5 in antiviral responses | journal = The Journal of Biological Chemistry | volume = 285 | issue = 34 | pages = 26223–26232 | date = August 2010 | pmid = 20538593 | pmc = 2924034 | doi = 10.1074/jbc.M110.109736 | doi-access = free }}{{cite journal | vauthors = Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF | title = NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways | journal = Cell | volume = 141 | issue = 3 | pages = 483–496 | date = April 2010 | pmid = 20434986 | pmc = 3150216 | doi = 10.1016/j.cell.2010.03.040 }}{{cite journal | vauthors = Kuenzel S, Till A, Winkler M, Häsler R, Lipinski S, Jung S, Grötzinger J, Fickenscher H, Schreiber S, Rosenstiel P | title = The nucleotide-binding oligomerization domain-like receptor NLRC5 is involved in IFN-dependent antiviral immune responses | journal = Journal of Immunology | volume = 184 | issue = 4 | pages = 1990–2000 | date = February 2010 | pmid = 20061403 | doi = 10.4049/jimmunol.0900557 | doi-access = free }} It also acts as an innate immune sensor to drive inflammatory cell death, PANoptosis.{{cite journal | vauthors = Sundaram B, Pandian N, Kim HJ, Abdelaal HM, Mall R, Indari O, Sarkar R, Tweedell RE, Alonzo EQ, Klein J, Pruett-Miller SM, Vogel P, Kanneganti TD | title = NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation | journal = Cell | volume = 187 | issue = 15 | pages = 4061–4077.e17 | date = July 2024 | doi = 10.1016/j.cell.2024.05.034 | pmid = 38878777 | pmc = 11283362 }}{{Cite web |date=2024-06-14 |title=St. Jude scientists solve decades long mystery of NLRC5 sensor function in cell death and disease |url=https://www.stjude.org/media-resources/news-releases/2024-medicine-science-news/scientists-solve-decades-long-mystery-of-nlrc5-sensor-function-in-cell-death.html |access-date=2024-08-13 |website=www.stjude.org}} In humans, the NLRC5 protein is encoded by the NLRC5 gene.{{cite journal | vauthors = Dowds TA, Masumoto J, Chen FF, Ogura Y, Inohara N, Núñez G | title = Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product | journal = Biochemical and Biophysical Research Communications | volume = 302 | issue = 3 | pages = 575–580 | date = March 2003 | pmid = 12615073 | doi = 10.1016/S0006-291X(03)00221-3 }} It has also been called NOD27, NOD4, and CLR16.1.
Structure
Structurally, NLRC5 has a putative caspase recruitment domain (CARD), followed by a NACHT domain, and a C-terminal leucine-rich repeat (LRR) region.
Function
Through its structural features, NLRC5 acts as a key regulator of Major Histocompatibility Class I (MHCI) molecule expression,{{cite journal | vauthors = Meissner TB, Li A, Biswas A, Lee KH, Liu YJ, Bayir E, Iliopoulos D, van den Elsen PJ, Kobayashi KS | title = NLR family member NLRC5 is a transcriptional regulator of MHC class I genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 31 | pages = 13794–13799 | date = August 2010 | pmid = 20639463 | pmc = 2922274 | doi = 10.1073/pnas.1008684107 | doi-access = free | bibcode = 2010PNAS..10713794M }} 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).{{cite journal | vauthors = Staehli F, Ludigs K, Heinz LX, Seguín-Estévez Q, Ferrero I, Braun M, Schroder K, Rebsamen M, Tardivel A, Mattmann C, MacDonald HR, Romero P, Reith W, Guarda G, Tschopp J | title = NLRC5 deficiency selectively impairs MHC class I- dependent lymphocyte killing by cytotoxic T cells | journal = Journal of Immunology | volume = 188 | issue = 8 | pages = 3820–3828 | date = April 2012 | pmid = 22412192 | doi = 10.4049/jimmunol.1102671 | doi-access = free }} In lymphocytes, NLRC5 localizes to the nucleus and drives MHCI gene expression by occupying H-2D and H-2K gene promoters.
NLRC5 also functions as an innate immune sensor that, upon NAD+ depletion, forms a PANoptosome, driving PANoptosis and inflammation. 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.{{cite journal | vauthors = Samir P, Malireddi RK, Kanneganti TD | title = The PANoptosome: A Deadly Protein Complex Driving Pyroptosis, Apoptosis, and Necroptosis (PANoptosis) | journal = Frontiers in Cellular and Infection Microbiology | volume = 10 | issue = | pages = 238 | date = 2020 | pmid = 32582562 | pmc = 7283380 | doi = 10.3389/fcimb.2020.00238 | doi-access = free }}{{cite journal | vauthors = Karki R, Kanneganti TD | title = PANoptosome signaling and therapeutic implications in infection: central role for ZBP1 to activate the inflammasome and PANoptosis | journal = Current Opinion in Immunology | volume = 83 | issue = | pages = 102348 | date = August 2023 | pmid = 37267644 | pmc = 10524556 | doi = 10.1016/j.coi.2023.102348 }} 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.
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References
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{{NOD-like receptors}}
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