Abstract
Homeostasis at mucosal surfaces requires cross-talk between the environment and barrier epithelial cells. Disruption of barrier function typifies mucosal disease. Here we elucidate a bifunctional role in coordinating this cross-talk for the inflammatory bowel disease risk-gene INAVA. Both activities require INAVA's DUF3338 domain (renamed CUPID). CUPID stably binds the cytohesin ARF-GEF ARNO to effect lateral membrane F-actin assembly underlying cell-cell junctions and barrier function. Unexpectedly, when bound to CUPID, ARNO affects F-actin dynamics in the absence of its canonical activity as a guanine nucleotide-exchange factor. Upon exposure to IL-1β, INAVA relocates to form cytosolic puncta, where CUPID amplifies TRAF6-dependent polyubiquitination and inflammatory signaling. In this case, ARNO binding to CUPID negatively-regulates polyubiquitination and the inflammatory response. INAVA and ARNO act similarly in primary human macrophages responding to IL-1β and to NOD2 agonists. Thus, INAVA-CUPID exhibits dual functions, coordinated directly by ARNO, that bridge epithelial barrier function with extracellular signals and inflammation.
Highlights
C1ORF106, recently named INAVA (Innate Immune Activator), was identified as a risk factor for the chronic inflammatory bowel diseases (IBD) by genome-wide association studies and targeted exome sequencing (Rivas et al, 2011)
These phenotypes are consistent with a recent study using INAVA knock-out mice that supports a role for INAVA in maintenance of intercellular epithelial junctions responsible for mucosal barrier function (Mohanan et al, 2018)
To understand how INAVA acts on epithelial junctions, we first examined the localization of INAVA constructs fused to GFP that were stably expressed in Caco2BBe cells
Summary
C1ORF106, recently named INAVA (Innate Immune Activator), was identified as a risk factor for the chronic inflammatory bowel diseases (IBD) by genome-wide association studies and targeted exome sequencing (Rivas et al, 2011). Mice lacking the protein altogether show defects in intestinal barrier integrity at steady state and greater susceptibility to mucosal infection (Mohanan et al, 2018). Human macrophages carrying the IBD rs7554511 risk allele have decreased INAVA expression and show multiple defects in myeloid function, including in innate immune NOD2 signaling and cytokine secretion, and in microbial clearance in association with reduced autophagy and ROS production (Yan et al, 2017). Each process is well known to affect gut function in health and disease, but the
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