CHIP as a membrane-shuttling proteostasis sensor
CHIP as a membrane-shuttling proteostasis sensor
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DOI：
10.7554/elife.29388
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发表时间：
2017-11-01
期刊：
影响因子：
7.7
通讯作者：
Vabulas, R. Martin
中科院分区：
文献类型：
--
作者：
Kopp, Yannick;Lang, Wei-Han;Vabulas, R. Martin
细胞通过调节基因转录和许多转录后过程来响应胞质溶胶中的蛋白质错误折叠和聚集。与功能反应平行，细胞结构也发生变化;然而，细胞隔室对胞质蛋白质错误折叠的早期适应机制尚不清楚。在这里，我们表明，哺乳动物泛素连接酶C-末端热休克蛋白70相互作用蛋白（CHIP），如果从伴侣在急性应激期间，可以停靠在细胞膜上，从而执行蛋白质稳态传感器功能。我们在体外重建了这一过程，发现主要是磷脂酸和磷脂酰肌醇-4-磷酸增强了无伴侣CHIP与脂质体的结合。HSP 70和膜竞争与CHIP的三肽重复结构域的互斥结合。在新的细胞位置，进入特定的隔室基板将使CHIP参与重组各自的细胞器，作为例子的高尔基体的碎片（效应器功能）。
Cells respond to protein misfolding and aggregation in the cytosol by adjusting gene transcription and a number of post-transcriptional processes. In parallel to functional reactions, cellular structure changes as well; however, the mechanisms underlying the early adaptation of cellular compartments to cytosolic protein misfolding are less clear. Here we show that the mammalian ubiquitin ligase C-terminal Hsp70-interacting protein (CHIP), if freed from chaperones during acute stress, can dock on cellular membranes thus performing a proteostasis sensor function. We reconstituted this process in vitro and found that mainly phosphatidic acid and phosphatidylinositol-4-phosphate enhance association of chaperone-free CHIP with liposomes. HSP70 and membranes compete for mutually exclusive binding to the tetratricopeptide repeat domain of CHIP. At new cellular locations, access to compartment-specific substrates would enable CHIP to participate in the reorganization of the respective organelles, as exemplified by the fragmentation of the Golgi apparatus (effector function).