Epithelial cells lining mucosal surfaces distinctively express the inflammatory bowel disease risk gene INAVA. We previously found that INAVA has dual and competing functions: one at lateral membranes where it affects mucosal barrier function and the other in the cytosol where INAVA enhances IL-1β signal transduction and protein ubiquitination and forms puncta. We now find that IL-1β–induced INAVA puncta are biomolecular condensates that rapidly assemble and physiologically resolve. The condensates contain ubiquitin and the E3 ligase βTrCP2, and their formation correlates with amplified ubiquitination, suggesting function in regulation of cellular proteostasis. Accordingly, a small-molecule screen identified ROS inducers, proteasome inhibitors, and inhibitors of the protein folding chaperone HSP90 as potent agonists for INAVA condensate formation. Notably, inhibitors of the p38α and mTOR pathways enhanced resolution of the condensates, and inhibitors of the Rho–ROCK pathway induced INAVA’s competing function by recruiting INAVA to newly assembled intercellular junctions in cells where none existed before.

中文翻译：

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INAVA 胞质凝聚物和细胞-细胞连接组件的小分子调节剂

粘膜表面的上皮细胞独特地表达炎症性肠病风险基因 INAVA。我们之前发现 INAVA 具有双重且相互竞争的功能：一个在侧膜，影响粘膜屏障功能；另一个在细胞质，INAVA 增强 IL-1β 信号转导和蛋白质泛素化并形成斑点。我们现在发现 IL-1β 诱导的 INAVA 斑点是快速组装和生理分解的生物分子凝聚物。缩合物含有泛素和 E3 连接酶 βTrCP2，它们的形成与放大的泛素化相关，表明其具有调节细胞蛋白质稳态的功能。因此，小分子筛选鉴定出 ROS 诱导剂、蛋白酶体抑制剂和蛋白质折叠伴侣 HSP90 抑制剂作为 INAVA 缩合物形成的有效激动剂。值得注意的是，p38α和mTOR途径的抑制剂增强了凝聚物的分辨率，而Rho-ROCK途径的抑制剂通过将INAVA招募到细胞中以前不存在的新组装的细胞间连接处来诱导INAVA的竞争功能。