Alternative titles; symbols
HGNC Approved Gene Symbol: NLRC3
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38) : 16:3,539,033-3,577,403 (from NCBI)
The NLR (nucleotide-binding, leucine-rich repeat (LRR)-containing) family of sensors has many functions, including inflammatory and antiinflammatory roles. NLRC3, an NLR family member, attenuates immune-cell activation by interacting with receptors or their downstream adaptors to inhibit signaling molecules (Schneider et al., 2012).
By searching databases for sequences related to CIITA (MHC2TA; 600005), Harton et al. (2002) obtained a partial sequence for NLRC3, which they called CLR16.2. Using primers based on this partial CLR16.2 sequence for RT-PCR of Raji lymphoma cell mRNA, followed by 5-prime and 3-prime RACE, Conti et al. (2005) isolated full-length CLR16.2. The predicted 1,065-amino acid protein lacks an N-terminal pyrin domain, but it has an N-terminal nucleotide-binding domain (NBD) and 14 C-terminal LRRs. RT-PCR analysis of human cell lines detected CLR16.2 expression in various immune cell lines, particularly in T cells, but showed poor expression in epithelial cell lines. Immunofluorescent microscopy demonstrated cytoplasmic expression in transfected HeLa cells.
Conti et al. (2005) determined that the CLR16.2 gene contains 15 coding exons. A large exon encodes the NBD, and 14 smaller exons encode the LRRs.
By genomic sequence analysis, Harton et al. (2002) mapped the CLR16.2 gene to chromosome 16p13.3.
Conti et al. (2005) found that expression of CLR16.2 in mitogen-stimulated human T cells resulted in decreased NFKB (see 164011), AP1 (165160), and NFAT (see 600490) activity and decreased CD25 (IL2RA; 147730) and IL2 (147680) expression. Decreased NFKB activation following CLR16.2 overexpression appeared to be due to altered IKBA (NFKBIA; 164008) degradation. Conti et al. (2005) proposed that CLR16.2 plays a role in attenuating T-cell activation.
Schneider et al. (2012) observed diminished NFKB signaling and reduced IL6 (147620) and TNF (191160) expression in a human monocyte cell line transfected with NLRC3 compared with nontransfected cells following stimulation with lipopolysaccharide (LPS). Reduced NFKB signaling was caused by NLRC3 associating via its NBD with the Toll-like receptor (TLR) signaling adaptor TRAF6 (602355) and altering TRAF6 ubiquitination. Schneider et al. (2012) proposed that NLRC3 affects TRAF6 ubiquitination and alters TLR signaling.
Zhang et al. (2014) found that Nlrc3 reduced Sting (TMEM173; 612374)-dependent innate immune function in mouse cells in response to cytosolic DNA, cyclic di-GMP, and DNA viruses. Mouse embryonic fibroblasts lacking Nlrc3 produced more Ifnb (147640) and Il6 in response to cyclic di-GMP-producing bacteria. Pull-down experiments with recombinant human NLRC3 and STING showed direct interaction between the proteins. The nucleotide-binding domain of NLRC3 associated with membrane-bound STING. NLRC3 interacted with the N terminus of TBK1 (604834) and impeded STING-TBK1 interaction and downstream type I interferon production. NLRC3 prevented correct trafficking of STING to perinuclear and punctate regions. Zhang et al. (2014) concluded that interaction of the NLR and STING pathways fine tunes the host response to intracellular DNA, cyclic di-GMP, and DNA viruses.
Schneider et al. (2012) generated healthy and fertile Nlrc3-deficient mice by homologous recombination. Stimulation of Nlrc3-deficient macrophages with LPS resulted in increased production of proinflammatory cytokines and greater activation of Traf6 and Nfkb compared with wildtype macrophages. Injection of a nonlethal dose of LPS into Nlrc3-deficient mice caused a greater drop in body temperature and more weight loss, as well as increased serum Tnf and, particularly, increased Il6, compared with wildtype mice. Schneider et al. (2012) concluded that NLRC3 plays a protective role in endotoxic shock.
Zhang et al. (2014) found that mice lacking Nlrc3 and infected with herpes simplex virus (HSV)-1 showed enhanced innate immune responses and reduced morbidity and viral load compared with infected wildtype mice. In contrast, wildtype mice and Nlrc3-deficient mice exhibited no significant differences following infection with vesicular stomatitis virus (VSV). Zhang et al. (2014) concluded that Nlrc3 attenuates the host response to HSV-1, a DNA virus, but not to VSV, an RNA virus.
Karki et al. (2016) showed that mice lacking NLRC3 are hypersusceptible to colitis and colorectal tumorigenesis. The effect of NLRC3 was most dominant in enterocytes, in which it suppressed activation of the mTOR (601231) signaling pathways and inhibited cellular proliferation and stem cell-derived organoid formation. NLRC3 associated with PI3Ks and blocked activation of the PI3K-dependent kinase AKT (164730) following binding of growth factor receptors or TLR4 (603030). Karki et al. (2016) concluded that their findings revealed a key role for NLRC3 as an inhibitor of the mTOR pathways, mediating protection against colorectal cancer.
Conti, B. J., Davis, B. K., Zhang, J., O'Connor, W., Jr., Williams, K. L., Ting, J. P.-Y. CATERPILLER 16.2 (CLR16.2), a novel NBD/LRR family member that negatively regulates T cell function. J. Biol. Chem. 280: 18375-18385, 2005. [PubMed: 15705585] [Full Text: https://doi.org/10.1074/jbc.M413169200]
Harton, J. A., Linhoff, M. W., Zhang, J., Ting, J. P.-Y. Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. J. Immun. 169: 4088-4093, 2002. [PubMed: 12370334] [Full Text: https://doi.org/10.4049/jimmunol.169.8.4088]
Karki, R., Man, S. M., Malireddi, R. K. S., Kesavardhana, S., Zhu, Q., Burton, A. R., Sharma, B. R., Qi, X., Pelletier, S., Vogel, P., Rosenstiel, P., Kanneganti, T.-D. NLRC3 is an inhibitory sensor of PI3K-mTOR pathways in cancer. Nature 540: 583-587, 2016. [PubMed: 27951586] [Full Text: https://doi.org/10.1038/nature20597]
Schneider, M., Zimmermann, A. G., Roberts, R. A., Zhang, L., Swanson, K. V., Wen, H., Davis, B. K., Allen, I. C., Holl, E. K., Ye, Z., Rahman, A. H., Conti, B. J., Eitas, T. K., Koller, B. H., Ting, J. P.-Y. The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-kappa-B. Nature Immun. 13: 823-831, 2012. [PubMed: 22863753] [Full Text: https://doi.org/10.1038/ni.2378]
Zhang, L., Mo, J., Swanson, K. V., Wen, H., Petrucelli, A., Gregory, S. M., Zhang, Z., Schneider, M., Jiang, Y., Fitzgerald, K. A., Ouyang, S., Liu, Z.-J., Damania, B., Shu, H.-B., Duncan, J. A., Ting, J. P.-Y. NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING. Immunity 40: 329-341, 2014. [PubMed: 24560620] [Full Text: https://doi.org/10.1016/j.immuni.2014.01.010]