C1orf106 is a colitis risk gene that regulates stability of epithelial adherens junctions

Science. 2018 Mar 9;359(6380):1161-1166. doi: 10.1126/science.aan0814. Epub 2018 Feb 1.

Abstract

Polymorphisms in C1orf106 are associated with increased risk of inflammatory bowel disease (IBD). However, the function of C1orf106 and the consequences of disease-associated polymorphisms are unknown. Here we demonstrate that C1orf106 regulates adherens junction stability by regulating the degradation of cytohesin-1, a guanine nucleotide exchange factor that controls activation of ARF6. By limiting cytohesin-1-dependent ARF6 activation, C1orf106 stabilizes adherens junctions. Consistent with this model, C1orf106-/- mice exhibit defects in the intestinal epithelial cell barrier, a phenotype observed in IBD patients that confers increased susceptibility to intestinal pathogens. Furthermore, the IBD risk variant increases C1orf106 ubiquitination and turnover with consequent functional impairments. These findings delineate a mechanism by which a genetic polymorphism fine-tunes intestinal epithelial barrier integrity and elucidate a fundamental mechanism of cellular junctional control.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / metabolism
  • Adherens Junctions / genetics*
  • Animals
  • Caco-2 Cells
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Inflammatory Bowel Diseases / genetics*
  • Intestinal Mucosa / pathology
  • Mice
  • Mice, Mutant Strains
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Polymorphism, Genetic
  • Proteolysis
  • Risk
  • Ubiquitination / genetics

Substances

  • C1orf109 protein, human
  • Guanine Nucleotide Exchange Factors
  • Phosphoproteins
  • cytohesin-1
  • ADP-Ribosylation Factors
  • ADP-ribosylation factor 6