Alternative titles; symbolsCHROMOSOME 1 OPEN READING FRAME 106; C1ORF106HGNC Approved Gene Symbol: INAVACytogenetic location: 1q32.1 Genomic coordinates (GRC...
Alternative titles; symbols
HGNC Approved Gene Symbol: INAVA
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:200,891,530-200,915,741 (from NCBI)
INAVA is required for optimal pattern recognition receptor (PRR)-induced signaling, cytokine secretion, and bacterial clearance (Yan et al., 2017). INAVA also regulates adherens junction stability by regulating degradation of cytohesin-1 (CYTH1; 182115) (Mohanan et al., 2018).
▼ Cloning and Expression
Using quantitative PCR, Yan et al. (2017) found that INAVA was highly expressed in human peripheral and intestinal myeloid cells.
By microarray analysis, Mohanan et al. (2018) found that INAVA was highly expressed in human intestine and intestinal epithelial cell lines. It was expressed at low levels in human myeloid cells and mouse bone marrow-derived macrophages. Immunoblot analysis of human colorectal cells showed that INAVA protein expression increased as cells differentiated and formed a polarized epithelial monolayer.
Mohanan et al. (2018) stated that the INAVA gene maps to chromosome 1q32.1.
▼ Gene Function
Yan et al. (2017) found that INAVA was required for optimal PRR-induced MAPK and NF-kappa-B (see 164011) activation, cytokine secretion, and bacterial clearance in primary human monocyte-derived macrophages. Upon NOD2 stimulation, INAVA translocated to nucleus, which required all 3 nuclear localization signals in INAVA. INAVA recruited 14-3-3-tau (YWHAQ; 609009) through its three 14-3-3-binding regions, leading to assembly of a signaling complex that amplified downstream PRR-induced signaling and cytokine secretion. Consistent with INAVA regulating both NOD2-induced MAPK and NF-kappa-B pathways, the authors showed that INAVA modulated a broad range of NOD2-induced transcripts.
Using tandem mass spectrometry-based affinity proteomics, followed by coimmunoprecipitation analysis of transfected and endogenous proteins in HEK293T and Caco2 cells, respectively, Mohanan et al. (2018) found that INAVA interacted with CYTH1 and CYTH2 (602488). Domain mapping experiments showed that INAVA and CYTH1 interacted through their respective N-terminal domains. Colon and small intestine epithelial cells from Inava -/- mice showed increased Cyth1 protein levels compared with cells from wildtype mice. Further analysis showed that Inava acted as a cofactor for an SCF ubiquitin ligase that dynamically regulated the steady-state levels of Cyth1 through ubiquitin-mediated proteasomal degradation. Increased levels of Cyth1 protein increased activated Arf6 (600464) (i.e., Arf6-GTP) levels in organoid-derived intestinal epithelial monolayers of Inava -/- mice compared with wildtype mice, despite comparable total levels of Arf6. Increased Cyth1 and Arf6-GTP levels in Inava -/- intestinal epithelial cells caused decreased localization of E-cadherin (CDH1; 192090) along the cell surface compared with wildtype cells, despite similar total expression of E-cadherin. Decreased surface localization of E-cadherin impaired epithelial barrier integrity, as the ability to repair epithelial junctions after injury was altered and Inava -/- cells became susceptible to intestinal pathogens.
▼ Molecular Genetics
Rivas et al. (2011) used pooled next-generation sequencing to study 56 genes from regions associated with Crohn disease (CD) in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in 9 independent case-control series (16,054 Crohn disease cases, 12,153 ulcerative colitis (UC) cases, and 17,575 healthy controls), they identified an independent risk allele in the C1ORF106 gene (Y333F; 618051.0001) for inflammatory bowel disease (IBD29; 618077).
Mohanan et al. (2018) demonstrated that the Y333F variant decreased INAVA protein stability through ubiquitination and subsequent degradation by the proteasome, thereby impairing the turnover and degradation of cytohesin-1.
Jostins et al. (2012) performed a metaanalysis of CD and UC genomewide association scans, with a combined total of more than 75,000 cases and controls, and found an association between inflammatory bowel disease and SNP rs7554511. Yan et al. (2017) stated that this polymorphism was located in an intronic region between exons 6 and 7 of the INAVA gene. Yan et al. (2017) found that monocyte-derived macrophages (MDMs) from the rs7554511 C risk carriers expressed lower levels of INAVA and demonstrated decreased signaling, cytokine secretion, and bacterial clearance upon stimulation with ligands for a broad range of pattern recognition receptors (PRRs).
▼ ALLELIC VARIANTS ( 1 Selected Example):
.0001 INFLAMMATORY BOWEL DISEASE 29
INAVA, TYR333PHE (rs41313912)
Rivas et al. (2011) used pooled next-generation sequencing to study 56 genes from regions associated with Crohn disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in 9 independent case-control series (16,054 Crohn disease cases, 12,153 ulcerative colitis cases, and 17,575 healthy controls), they identified tyr333-to-phe (Y333F) in the C1ORF106 gene as an independent risk factor for inflammatory bowel disease (p = 0.009) (IBD29; 618077).
Mohanan et al. (2018) showed that expression of the C1ORF106 Y333F allele (which they called *333F) was reproducibly decreased during transient transfection compared with that of wildtype C1ORF106, despite comparable levels of mRNA, suggesting that the risk variant is poorly expressed or unstable. To test whether decreased levels of Y333F were due to ubiquitination degradation by the proteosome, Mohanan et al. (2018) treated cells with the protease inhibitor MG132, which restored Y333F protein levels to wildtype levels. In addition, ubiquitination of C1ORF106 carrying the Y333F variant was increased compared with wildtype, suggesting that the polymorphism increases protein turnover of C1ORF106, resulting in decreased expression of functional protein. Consistent with these results, the variant was found to have a half-life of 10.2 hours compared to a wildtype half-life of almost 17 hours. Mohanan et al. (2018) suggested a mechanism by which the Y333F polymorphism decreases C1ORF106 protein stability and thus confers increased susceptibility to IBD by compromising gut epithelial integrity through impaired turnover and degradation of cytohesin-1.