Alternative titles; symbolsNACHT DOMAIN-, LEUCINE-RICH REPEAT-, AND PYD-CONTAINING PROTEIN 10; NALP10PYNODNOD8HGNC Approved Gene Symbol: NLRP10Cytogenetic locati...
Alternative titles; symbols
HGNC Approved Gene Symbol: NLRP10
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:7,957,536-7,965,446 (from NCBI)
NALPs are cytoplasmic proteins that form a subfamily within the larger CATERPILLER protein family. Most short NALPs have an N-terminal pyrin (MEFV; 608107) domain (PYD), followed by a NACHT domain, a NACHT-associated domain (NAD), and a C-terminal leucine-rich repeat (LRR) region. NALP10, however, lacks the LRR region. The long NALP, NALP1 (606636), also has a C-terminal extension containing a function to find domain (FIIND) and a caspase recruitment domain (CARD). NALPs are implicated in the activation of proinflammatory caspases (e.g., CASP1; 147678) via their involvement in multiprotein complexes called inflammasomes (Tschopp et al., 2003).
▼ Cloning and Expression
By searching databases for homologs of PYPAF1 (NALP3, or CIAS1; 606416), followed by RT-PCR of a heart cDNA library, Wang et al. (2004) cloned NALP10, which they termed PYNOD. The predicted 655-amino acid protein contains an N-terminal PYD and C-terminal nucleotide-binding oligomerization domain (NOD), but no LRR. It shares approximately 55% amino acid identity with rat and mouse Nalp10. Northern blot analysis revealed a 2.4-kb transcript in all tissues examined, with high expression in brain, heart, and skeletal muscle. A 4.4-kb transcript was also expressed in brain, heart, and skeletal muscle. NALP10 expression was also detected in various cell lines, including those of hemopoietic lineage.
▼ Gene Function
Wang et al. (2004) found that NALP10 expression was enhanced by stimulation with lipopolysaccharide. NALP10 inhibited NFKB (see 164011) activation and apoptosis induced by ASC (PYCARD; 606838) in a dose-dependent manner. Immunoprecipitation analysis showed that NALP10 interacted with ASC, CASP1, and IL1B (147720). Wang et al. (2004) proposed that NALP10 plays a regulatory role in the innate immune system.
▼ Gene Structure
Wang et al. (2004) determined that the NALP10 gene contains 2 exons and spans about 4.5 kb.
By genomic sequence analysis, Wang et al. (2004) mapped the NALP10 gene to chromosome 11p15.
▼ Animal Model
Eisenbarth et al. (2012) generated Nlrp10 knockout mice and did not find evidence that NLRP10 functions through an inflammasome to regulate caspase-1 (147678) activity nor that it regulates other inflammasomes. Instead, Eisenbarth et al. (2012) found that Nlrp10-null mice had a profound defect in helper T-cell-driven immune responses to a diverse array of adjuvants, including lipopolysaccharide, aluminum hydroxide, and complete Freund adjuvant. Originally, it was thought that adaptive immunity was impaired in the absence of Nlrp10 because of a dendritic cell intrinsic defect in emigration from inflamed tissues, whereas upregulation of dendritic cell costimulatory molecules and chemotaxis to Ccr7 (600242)-dependent and -independent ligands remained intact. However, in a correction, after backcrossing of mutant mice to mice of different backgrounds, followed by whole-exome sequencing, In an erratum, the authors reported that DC migration is in fact dependent on Dock8 (611432), a mutation in which apparently developed after the generation of the Nlrp10 -/- strain and subsequent intercrossing. The authors confirmed that Nlrp10 loss does not result in enhanced Nlrp3 (606416) inflammasome activation, and that aberrant Gdpd3 (616318) upregulation is due to Nlrp10 loss and not to Dock8 deficiency. The loss of antigen transport to the draining lymph nodes by a subset of migratory dendritic cells, due to loss of Dock8, resulted in almost absolute loss in naive Cd4+ (186940) T-cell priming, highlighting the critical link between diverse innate immune stimulation, NLRP10 activity, and immune function of mature dendritic cells. The authors also concluded that there is a need for continual evaluation of genetic stability of inbred mouse strains and for periodically obtaining new breeding stock from founder lines or early-generation cryopreserved embryos.
Joly et al. (2012) found that, like Nlrp3 -/- mice, Nlrp10 -/- mice were highly susceptible to infection with Candida albicans. Mice lacking other NLR family members similar to Nlrp3 showed no increased susceptibility. Following fungal invasion of kidneys, renal dysfunction was observed in Nlrp10 -/- mice. Unlike Nlrp3 -/- mice, Nlrp10 -/- mice produced levels of Il1b comparable to wildtype and had no loss of phagocytic or intracellular killing capacity. However, generation of both Th1 and Th17 Candida-specific responses required Nlrp10. Joly et al. (2012) concluded that NLRP10 is involved in the generation of antifungal adaptive immune responses.