Inositol Polyphosphate Multikinase Inhibits Liquid-Liquid Phase Separation of TFEB to Negatively Regulate Autophagy Activity
Inositol Polyphosphate Multikinase Inhibits Liquid-Liquid Phase Separation of TFEB to Negatively Regulate Autophagy Activity
复制标题
肌醇多磷酸多激酶抑制TFEB液-液相分离负向调节自噬活性
DOI：
10.1016/j.devcel.2020.10.010
复制
发表时间：
2020-12-07
影响因子：
11.8
通讯作者：
Zhang, Hong
中科院分区：
文献类型：
--
作者：
Chen, Di;Wang, Zheng;Zhang, Hong
液-液相分离（LLPS）将基因表达的转录凝聚物区隔，但对这一过程是如何控制的知之甚少。在这里，我们发现编码肌醇多磷酸多激酶的IPMK的缺失，以tfeb依赖的方式促进自噬和溶酶体功能和生物发生。TFEB的细胞质-核转运是多种信号通路调节TFEB活性的一种特征明确的机制，IPMK耗竭不会明显改变TFEB的转运。我们证明核TFEB形成不同的点，与介质复合物和靶溶酶体基因的mrna共定位。TFEB在体外经历LLPS。IPMK直接与TFEB的LLPS相互作用，抑制TFEB的LLPS，并溶解TFEB凝析物。IPMK的缺失增加了核TFEB点的数量，并增加了TFEB与靶基因的中介和mrna的共定位。我们的研究表明，核定位IPMK作为伴侣抑制TFEB的LLPS，负向控制其转录活性。
Liquid-liquid phase separation (LLPS) compartmentalizes transcriptional condensates for gene expression, but little is known about how this process is controlled. Here, we showed that depletion of IPMK, encoding inositol polyphosphate multikinase, promotes autophagy and lysosomal function and biogenesis in a TFEB-dependent manner. Cytoplasmic-nuclear trafficking of TFEB, a well-characterized mechanism by which diverse signaling pathways regulate TFEB activity, is not evidently altered by IPMK depletion. We demonstrated that nuclear TFEB forms distinct puncta that colocalize with the Mediator complex and with mRNAs of target lysosomal genes. TFEB undergoes LLPS in vitro. IPMK directly interacts with and inhibits LLPS of TFEB and also dissolves TFEB condensates. Depletion of IPMK increases the number of nuclear TFEB puncta and the co-localization of TFEB with Mediator and mRNAs of target genes. Our study reveals that nuclear-localized IPMK acts as a chaperone to inhibit LLPS of TFEB to negatively control its transcriptional activity.