NLRP11

NOD-like receptor family pyrin domain containing 11 is a protein that in humans is encoded by the NLRP11 gene located on the long arm of human chromosome 19q13.42. NLRP11 belongs to the NALP subfamily, part of a large subfamily of CATERPILLER. It is also known as NALP11, PYPAF6, NOD17, PAN10, and CLR19.6

NLRP11
Identifiers
Aliases	NLRP11, CLR19.6, NALP11, NOD17, PAN10, PYPAF6, PYPAF7, NLR family, pyrin domain containing 11, NLR family pyrin domain containing 11
External IDs	OMIM: 609664; HomoloGene: 64817; GeneCards: NLRP11; OMA:NLRP11 - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.42-q13.43 Start 55,785,397 bp[1] End 55,836,800 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte testicle gonad right lobe of liver right testis islet of Langerhans left testis lymph node gallbladder renal cortex n/a More reference expression data BioGPS n/a
Orthologs Species Human Mouse Entrez 204801 n/a Ensembl ENSG00000179873 n/a UniProt P59045 n/a RefSeq (mRNA) NM_145007 NM_001297743 n/a RefSeq (protein) NP_001284672 NP_659444 n/a Location (UCSC) Chr 19: 55.79 – 55.84 Mb n/a PubMed search [2] n/a
Wikidata
View/Edit Human

Being a member of the NOD-like receptor protein (NLRP) gene family, it encodes a protein with an N-terminal pyrin death (PYD) domain and nucleoside triphosphate hydrolase (NACHT) domain and a C-terminal leucine-rich repeats (LRR) region. This gene regulates caspases in the proinflammatory signal transduction pathway. Based on studies of other members of the NLRP gene family with similar domain structures, it is predicted to form part of the multiprotein inflammasome complex.^[3][4]

NLRP11 is expressed mainly in immune cells, B cells, myeloid cells, and B cell lymphoma cell lines. NLRP11 is involved in the regulation of inflammatory responses in human cells.^[5]

NALPs family controls cytokines, inflammatory responses, NF-κB activation, and likely cell death and survival.^[6]

Structure

This gene encodes a protein with an N-terminal pyrin death (PYD) domain and nucleoside triphosphate hydrolase (NACHT) domain, and a C-terminal leucine-rich repeats (LRR) region. It contains a total of 14 LRRs and 1033 amino acids.^[3][4]

Evolution

NLRP11 is a primate-specific gene and is not found in mice A study on the evolution of mammalian reproduction-related NLRPs found that NLRP11 is part of a family cluster of genes that duplicated before the divergence of mammals.^[7]

Function

Bacterial lipopolysaccharide (LPS) is an endotoxin that can lead to lethal infection sepsis by activating innate immune responses. Cytoplasmic LPS(cLPS) induces the assembly of an inflammasome that contains caspases-4/5 in humans or caspase-11 in mice NLRP11 serves as a pattern recognition receptor for cLPS and can result in caspase-4 inflammasome activation.^[8]

There is also a novel role of NLRP11 in the regulation of inflammatory responses in human cells. In primates, NLRP11 also serves as a conserved negative regulator of TLR signaling. NLRP11 acts as a negative regulator of type I IFN and virus-induced apoptosis by disrupting the Mitochondrial antiviral-signaling protein (MAVS) signalosome activity. ATP-dependent RNA helicase DDX3X is a novel binding partner of NLRP11. NLRP11 suppressed the positive effect of DDX3X on NLRP3 inflammasome-mediated caspase-1 activation. Research also suggested that there might be a role of NLRP11 function in innate immunity. NLRP11 and DDX3X might become promising targets for the modulation of innate immune responses.^[9]

Upon viral infection, Type I IFN activates NLRP11, and upon activation, it translocates to mitochondria to interact with MAVS. NLRP11 degrades TRAF6 using MAVS to attenuate the production of type I IFNs and virus-induced apoptosis. NLRP11 acts as a negative regulator of type I IFN and virus-induced apoptosis via disrupting the activity of MAVS signalosome.^[10]

In human macrophages, NLRP11 is an indispensable component of the NLRP3 inflammasome. The most studied inflammasome sensor molecule of the NLR family is NLRP3, and it contains an amino-terminal PYRIN (PYD) domain, a nucleotide-binding NACHT domain, and a carboxyterminal leucine-rich repeat (LRR) domain. The ATP binding is required for NLRP3 activation, NACHT domain of NLRP3 contains ATPase activity, and mutation of this site reduces ATP binding, caspase-1 activation, IL-1 production, cell death, macromolecular complex formation, and its association with apoptosis-associated speck-like protein containing a CARD (ASC).

There is an interaction between NLRP11, NLRP3, and ASC. NLRP3 inflammasome activation is inhibited by specific deletion of NLRP11, which leads to inhibition of ASC polymerization, caspase-1 activation, and subsequent cytokine release. NLRP3 mutations that cause cryopyrin-associated periodic syndrome (CAPS) also require NLRP11 for inflammasome responses. The complex biology of inflammasome regulation is being explored, and the role of NLRP11 in diseases is partially understood.^[11]

References

1. GRCh38: Ensembl release 89: ENSG00000179873 – Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "NLRP11 NLR family pyrin domain containing 11 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2023-02-21.
4. Tschopp J, Martinon F, Burns K (February 2003). "NALPs: a novel protein family involved in inflammation". Nature Reviews. Molecular Cell Biology. 4 (2): 95–104. doi:10.1038/nrm1019. PMID 12563287. S2CID 31417018.
5. Ellwanger K, Becker E, Kienes I, Sowa A, Postma Y, Cardona Gloria Y, et al. (February 2018). "The NLR family pyrin domain-containing 11 protein contributes to the regulation of inflammatory signaling". The Journal of Biological Chemistry. 293 (8): 2701–2710. doi:10.1074/jbc.RA117.000152. PMC 5827450. PMID 29301940.
6. Harton JA, Linhoff MW, Zhang J, Ting JP (October 2002). "Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains". Journal of Immunology. 169 (8): 4088–4093. doi:10.4049/jimmunol.169.8.4088. PMID 12370334. S2CID 40372566.
7. Tian X, Pascal G, Monget P (August 2009). "Evolution and functional divergence of NLRP genes in mammalian reproductive systems". BMC Evolutionary Biology. 9 (1): 202. Bibcode:2009BMCEE...9..202T. doi:10.1186/1471-2148-9-202. PMC 2735741. PMID 19682372.
8. Rojas-Lopez M, Zajac AS, Wood TE, Miller KA, Gil-Marqués ML, Hachey AC, et al. (2022-06-15). "Pattern Recognition Receptor for Bacterial Lipopolysaccharide in the Cytosol of Human Macrophages". bioRxiv 10.1101/2021.10.22.465470.
9. Kienes I, Bauer S, Gottschild C, Mirza N, Pfannstiel J, Schröder M, Kufer TA (2021). "DDX3X Links NLRP11 to the Regulation of Type I Interferon Responses and NLRP3 Inflammasome Activation". Frontiers in Immunology. 12: 653883. doi:10.3389/fimmu.2021.653883. PMC 8158815. PMID 34054816.
10. Qin Y, Su Z, Wu Y, Wu C, Jin S, Xie W, et al. (December 2017). "NLRP11 disrupts MAVS signalosome to inhibit type I interferon signaling and virus-induced apoptosis". EMBO Reports. 18 (12): 2160–2171. doi:10.15252/embr.201744480. PMC 5709773. PMID 29097393.
11. Gangopadhyay A, Devi S, Tenguria S, Carriere J, Nguyen H, Jäger E, et al. (June 2022). "NLRP3 licenses NLRP11 for inflammasome activation in human macrophages". Nature Immunology. 23 (6): 892–903. doi:10.1038/s41590-022-01220-3. PMC 9174058. PMID 35624206.

Further reading

• 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.
• Enjuanes A, Benavente Y, Bosch F, Martín-Guerrero I, Colomer D, Pérez-Alvarez S, et al. (December 2008). "Genetic variants in apoptosis and immunoregulation-related genes are associated with risk of chronic lymphocytic leukemia". Cancer Research. 68 (24): 10178–10186. doi:10.1158/0008-5472.CAN-08-2221. PMID 19074885.
• Baranzini SE, Wang J, Gibson RA, Galwey N, Naegelin Y, Barkhof F, et al. (February 2009). "Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis". Human Molecular Genetics. 18 (4): 767–778. doi:10.1093/hmg/ddn388. PMC 4334814. PMID 19010793.
• Grenier JM, Wang L, Manji GA, Huang WJ, Al-Garawi A, Kelly R, et al. (October 2002). "Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-kappaB and caspase-1". FEBS Letters. 530 (1–3): 73–78. Bibcode:2002FEBSL.530...73G. doi:10.1016/S0014-5793(02)03416-6. PMID 12387869. S2CID 25023390.
• Wang L, Manji GA, Grenier JM, Al-Garawi A, Merriam S, Lora JM, et al. (August 2002). "PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing". The Journal of Biological Chemistry. 277 (33): 29874–29880. doi:10.1074/jbc.M203915200. PMID 12019269.