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Cytohesin Ubiquitin Protein Inducing Domain C1ORF106 also known as INAVA (Innate Immune Activator), is identified as a risk factor for the chronic inflammatory bowel diseases (IBD). Mice lacking the protein show defects in intestinal barrier integrity at steady state and greater susceptibility to mucosal infection. INAVA carries CUPID (Cytohesin Ubiquitin Protein Inducing Domain). Three other human proteins contain CUPID: FRMD4A, FRMD4B, and CCDC120- proteins implicated in neurite outgrowth, and in human cancer, Alzheimer's, celiac, and heart disease. All appear to bind the ARF-GEF (guanine nucleotide-exchange factors) cytohesin family members, such as proteins (ARF 1-4), which regulate cell membrane and F-actin dynamics. INAVA-CUPID binds cytohesin 2 (also known as ARNO), targets the molecule to lateral membranes of epithelial monolayers, and enables ARNO to affect F-actin assembly that underlies cell-cell junctions and barrier function. In the case of inflammatory signalling, ARNO can coordinate CUPID function by binding and inhibiting CUPID activity of acting as an enhancer of TRAF6 dependent polyubiquitination. In other words, ARNO acts as a negative-regulator of inflammatory responses. In summary, INAVA-CUPID exhibits dual functions, coordinated directly by ARNO, that bridge epithelial barrier function with extracellular signals and inflammation. |
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