Jiang, Xiaomo (2018) INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling. ELife., 7. ISSN 2050-084X

Abstract

The inflammatory bowel disease risk-gene INAVA is associated with regulation of
epithelial barrier integrity and innate immune signaling. Here, we define the molecular basis for
INAVA in epithelial F-actin assembly and inflammation. INAVA acts through its DUF3338
domain (renamed CUPID) to bind and recruit ARNO, a cytohesin ARF-GEF member, to lateral
membranes and enhance cortical F-actin assembly. Strikingly, this process is GEF activity
independent, implicating a novel and non-canonical mechanism for cytohesins. We find a second
function for INAVA in enhancing polyubiquitination in innate immune signaling cascades
downstream of IL-1β and NOD2. In this case, ARNO binding inhibits CUPID activity to
negatively-regulate inflammatory responses. Thus, INAVA exhibits dual functions coordinated
directly by ARNO that bridge epithelial barriers with inflammatory signaling at mucosal surfaces.

Item Type:	Article
Date Deposited:	04 Dec 2018 00:45
Last Modified:	04 Dec 2018 00:45
URI:	https://oak.novartis.com/id/eprint/36195