NLRC5

NLRC5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2MJM
Identifiers
Aliases	NLRC5, CLR16.1, NOD27, NOD4, NLR family, CARD domain containing 5, NLR family CARD domain containing 5
External IDs	OMIM: 613537; MGI: 3612191; HomoloGene: 88935; GeneCards: NLRC5; OMA:NLRC5 - orthologs
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16q13 Start 56,989,485 bp[1] End 57,083,531 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8|8 C5 Start 95,160,984 bp[2] End 95,253,900 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte spleen bone marrow cells blood appendix lymph node monocyte mucosa of ileum trabecular bone epithelium of nasopharynx Top expressed in mesenteric lymph nodes subcutaneous adipose tissue blood spleen submandibular gland thymus Paneth cell lens white adipose tissue skin of abdomen More reference expression data BioGPS n/a
Gene ontology Molecular function nucleotide binding protein binding ATP binding RNA polymerase II cis-regulatory region sequence-specific DNA binding Cellular component cytoplasm centrosome nucleus cytosol Biological process positive regulation of type I interferon-mediated signaling pathway negative regulation of type I interferon production positive regulation of interferon-gamma-mediated signaling pathway positive regulation of MHC class I biosynthetic process positive regulation of transcription by RNA polymerase II regulation of kinase activity immune system process innate immune response negative regulation of NF-kappaB transcription factor activity negative regulation of type I interferon-mediated signaling pathway response to bacterium intracellular signal transduction Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 84166 434341 Ensembl ENSG00000140853 ENSMUSG00000074151 UniProt Q86WI3 C3VPR6 RefSeq (mRNA) NM_032206 NM_001330552 NM_001033207 RefSeq (protein) NP_001317481 NP_115582 NP_001028379 Location (UCSC) Chr 16: 56.99 – 57.08 Mb Chr 8: 95.16 – 95.25 Mb PubMed search [3] [4]
Wikidata
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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

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,[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

1. GRCh38: Ensembl release 89: ENSG00000140853 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000074151 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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.
6. 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.
7. 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.
8. 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.
9. "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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.