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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\u2019s 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-1\u03b2, 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-1\u03b2 and to NOD2 agonists. Thus, INAVA-CUPID exhibits dual functions, coordinated directly by ARNO, that bridge epithelial barrier function with extracellular signals and inflammation.<\/jats:p>","DOI":"10.7554\/elife.38539","type":"journal-article","created":{"date-parts":[[2018,10,25]],"date-time":"2018-10-25T08:01:47Z","timestamp":1540454507000},"source":"Crossref","is-referenced-by-count":27,"title":["INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling"],"prefix":"10.7554","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1642-7415","authenticated-orcid":true,"given":"Phi","family":"Luong","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Nutrition and Hepatology, Boston Children\u2019s Hospital, Boston, United States"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, United 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