INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling
- Harvard Medical School, United States
- Yale University, United States
- Novartis Institutes for Biomedical Research, United States
- Massachusetts General Hospital, United States
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 NOD2 agonists. Thus, INAVA-CUPID exhibits dual functions, coordinated directly by ARNO, that bridge epithelial barrier function with extracellular signals and inflammation.
Data availability
All data analysed during this study are included in the manuscript. Source data have been provided for Figure 3 C-F.
Article and author information
Author details
Funding
National Institutes of Health (T32HD007466)
- Phi H Luong
Crohn's and Colitis Foundation of America (Career Development Award)
- Phi H Luong
Boston Children's Hospital (Rubin-Wolpow Fellowship)
- Phi H Luong
National Institutes of Health (DK099097)
- Clara Abraham
National Institutes of Health (DK048106)
- Wayne I Lencer
National Institutes of Health (DK084424)
- Wayne I Lencer
National Institutes of Health (P30 DK034854)
- Wayne I Lencer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Luong et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling
eLife 7:e38539.
https://doi.org/10.7554/eLife.38539
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