Division of Gastroenterology, Nutrition and Hepatology, Boston Children's Hospital, Boston, United States.
Department of Pediatrics, Harvard Medical School, Boston, United States.
Elife. 2018 Oct 25;7:e38539. doi: 10.7554/eLife.38539.
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 . 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.
黏膜表面的稳态需要环境和屏障上皮细胞之间的串扰。屏障功能的破坏是黏膜疾病的典型特征。在这里，我们阐明了炎症性肠病风险基因 在协调这种串扰方面的双重功能。这两种活性都需要 INAVA 的 DUF3338 结构域（重新命名为 CUPID）。CUPID 稳定地结合胞质溶胶 ARF-GEF ARNO，以影响细胞-细胞连接处和屏障功能的侧膜 F-肌动蛋白组装。出乎意料的是，当与 CUPID 结合时，ARNO 在没有其作为鸟嘌呤核苷酸交换因子的典型活性的情况下影响 F-肌动蛋白动力学。在暴露于 IL-1β 后，INAVA 重新定位形成胞质斑点，其中 CUPID 扩增 TRAF6 依赖性多泛素化和炎症信号。在这种情况下，ARNO 与 CUPID 的结合负调节多泛素化和炎症反应。INAVA 和 ARNO 在对 IL-1β 和 NOD2 激动剂作出反应的原代人巨噬细胞中发挥类似的作用。因此，INAVA-CUPID 表现出双重功能，直接由 ARNO 协调，将上皮屏障功能与细胞外信号和炎症联系起来。
