The Colitis Risk Gene C1orf106 (ROCS) Regulates Epithelial Adherens Junction Stability
Summary by Katie Golden
With the recent technical advances in genetic sequencing, a number of genes and polymorphisms have been identified that confer increased risk for Inflammatory Bowel Disease (IBD). Scientific research has not yet elucidated, however, the mechanisms through which these genes promote the pathophysiology of IBD. In this paper, investigators studied the specific gene C1orf106, and describe the pathways through which the IBD risk variant leads to colitis. The key is the gene’s role in maintaining intestinal epithelial barrier integrity.
Prior research has highlighted the abnormal intestinal permeability in patients with IBD. Functioning epithelial cells are necessary for nutrient absorption, barrier protection against microbes, and intestinal restoration following cellular insult. C1orf106 is highly expressed in human intestinal epithelial cells, and a formerly identified coding variant of the gene is known to be implicated in IBD. Here, researchers describe how the risk variant of the gene decreases cellular junctional integrity.
The investigators used mass spectrometry to identify proteins that interact with the gene, and then generated C1orf106 knockout mice to study how these proteins interact with the gene in a physiologically active model. They identified a specific protein, cytohesin-1, that exhibited aberrantly increased levels in the absence of a normally functioning C1orf106 gene (more specifically, that this protein did not undergo a molecularly complicated pathway that led to ubiquitin-mediated degradation). The increased levels of cytohesin-1, they found, leads to downstream dysregulation of enzymes and proteins (ARF6 and E-cadherin, to be specific) that play a critical role in maintaining adheren junctions between intestinal epithelial cells. The investigators ultimately observed how the risk variant gene resulted in impaired epithelial barrier integrity and increased permeability (which they observed and verified in their knockout mice models). When these knockout mice were exposed to bacteria, they had increased gut translocation of microbial pathogens, increased bacterial loads, and poor recovery from resultant colitis as evidenced by weight loss, reduced colon length, and severe histopathology abnormalities.
This paper expounds a critical connection between an identified risk variant gene and the development of IBD. By systematically studying and describing this mechanism, researchers have made headway in our understanding of IBD pathophysiology, and in turn opened the door for future therapeutic targets.