Center for Developmental Biology, School of Life Sciences, Anhui Agricultural University, Hefei, Anhui, 230036, China; State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing, 100101, China.
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing, 100101, China; School of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
Mol Cell. 2019 Apr 18;74(2):363-377.e5. doi: 10.1016/j.molcel.2019.02.004. Epub 2019 Mar 14.
In eukaryotic cells, RNA-binding proteins (RBPs) interact with RNAs to form ribonucleoprotein complexes (RNA granules) that have long been thought to regulate RNA fate or activity. Emerging evidence suggests that some RBPs not only bind RNA but also possess enzymatic activity related to ubiquitin regulation, raising important questions of whether these RBP-formed RNA granules regulate ubiquitin signaling and related biological functions. Here, we show that Drosophila Otu binds RNAs and coalesces to membrane-less biomolecular condensates via its intrinsically disordered low-complexity domain, and coalescence represents a functional state for Otu exerting deubiquitinase activity. Notably, coalescence-mediated enzymatic activity of Otu is positively regulated by its bound RNAs and co-partner Bam. Further genetic analysis reveals that the Otu/Bam deubiquitinase complex and dTraf6 constitute a feedback loop to maintain intestinal immune homeostasis during aging, thereby controlling longevity. Thus, regulated biomolecular condensates may represent a mechanism that controls dynamic enzymatic activities and related biological processes.
在真核细胞中，RNA 结合蛋白（RBPs）与 RNA 相互作用，形成核糖核蛋白复合物（RNA 颗粒），这些复合物长期以来被认为可以调节 RNA 的命运或活性。新出现的证据表明，一些 RBPs 不仅结合 RNA，还具有与泛素调节相关的酶活性，这就提出了一个重要的问题，即这些 RBP 形成的 RNA 颗粒是否调节泛素信号和相关的生物学功能。在这里，我们表明 Drosophila Otu 通过其固有无序的低复杂度结构域与 RNA 结合，并凝聚成无膜生物分子凝聚物，凝聚代表了 Otu 发挥去泛素化酶活性的功能状态。值得注意的是，Otu 的凝聚介导的酶活性受到其结合的 RNA 和共同伴侣 Bam 的正向调节。进一步的遗传分析表明，Otu/Bam 去泛素化酶复合物和 dTraf6 构成一个反馈回路，以维持衰老过程中肠道免疫的动态平衡，从而控制寿命。因此，受调控的生物分子凝聚物可能代表了一种控制动态酶活性和相关生物学过程的机制。
