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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.[5][6][7] It also acts as an innate immune sensor to drive inflammatory cell death, PANoptosis.[8][9] In humans, the NLRC5 protein is encoded by the NLRC5 gene.[10] It has also been called NOD27, NOD4, and CLR16.1.
Structure
[edit]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]Through its structural features, NLRC5 acts as a key regulator of Major Histocompatibility Class I (MHCI) molecule expression,[11] 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).[12] In lymphocytes, NLRC5 localizes to the nucleus and drives MHCI gene expression by occupying H-2D and H-2K gene promoters.[12]
NLRC5 also functions as an innate immune sensor that, upon NAD+ depletion, forms a PANoptosome, driving PANoptosis and inflammation.[8][9] 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.[13][14] 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.[8][9]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000140853 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000074151 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Neerincx A, Lautz K, Menning M, Kremmer E, Zigrino P, Hösel M, et al. (August 2010). "A role for the human nucleotide-binding domain, leucine-rich repeat-containing family member NLRC5 in antiviral responses". The Journal of Biological Chemistry. 285 (34): 26223–26232. doi:10.1074/jbc.M110.109736. PMC 2924034. PMID 20538593.
- ^ Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, et al. (April 2010). "NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways". Cell. 141 (3): 483–496. doi:10.1016/j.cell.2010.03.040. PMC 3150216. PMID 20434986.
- ^ Kuenzel S, Till A, Winkler M, Häsler R, Lipinski S, Jung S, et al. (February 2010). "The nucleotide-binding oligomerization domain-like receptor NLRC5 is involved in IFN-dependent antiviral immune responses". Journal of Immunology. 184 (4): 1990–2000. doi:10.4049/jimmunol.0900557. PMID 20061403.
- ^ a b c Sundaram B, Pandian N, Kim HJ, Abdelaal HM, Mall R, Indari O, et al. (July 2024). "NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation". Cell. 187 (15): 4061–4077.e17. doi:10.1016/j.cell.2024.05.034. PMC 11283362. PMID 38878777.
- ^ a b c "St. Jude scientists solve decades long mystery of NLRC5 sensor function in cell death and disease". www.stjude.org. 2024-06-14. Retrieved 2024-08-13.
- ^ Dowds TA, Masumoto J, Chen FF, Ogura Y, Inohara N, Núñez G (March 2003). "Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product". Biochemical and Biophysical Research Communications. 302 (3): 575–580. doi:10.1016/S0006-291X(03)00221-3. PMID 12615073.
- ^ Meissner TB, Li A, Biswas A, Lee KH, Liu YJ, Bayir E, et al. (August 2010). "NLR family member NLRC5 is a transcriptional regulator of MHC class I genes". Proceedings of the National Academy of Sciences of the United States of America. 107 (31): 13794–13799. Bibcode:2010PNAS..10713794M. doi:10.1073/pnas.1008684107. PMC 2922274. PMID 20639463.
- ^ a b Staehli F, Ludigs K, Heinz LX, Seguín-Estévez Q, Ferrero I, Braun M, et al. (April 2012). "NLRC5 deficiency selectively impairs MHC class I- dependent lymphocyte killing by cytotoxic T cells". Journal of Immunology. 188 (8): 3820–3828. doi:10.4049/jimmunol.1102671. PMID 22412192.
- ^ Samir P, Malireddi RK, Kanneganti TD (2020). "The PANoptosome: A Deadly Protein Complex Driving Pyroptosis, Apoptosis, and Necroptosis (PANoptosis)". Frontiers in Cellular and Infection Microbiology. 10: 238. doi:10.3389/fcimb.2020.00238. PMC 7283380. PMID 32582562.
- ^ Karki R, Kanneganti TD (August 2023). "PANoptosome signaling and therapeutic implications in infection: central role for ZBP1 to activate the inflammasome and PANoptosis". Current Opinion in Immunology. 83 102348. doi:10.1016/j.coi.2023.102348. PMC 10524556. PMID 37267644.
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