Hsp70-Bag3 complex is a hub for proteotoxicity-induced signaling that controls protein aggregation

Meriin Anatoli B.; Narayanan Arjun; Meng LeAlexandrov IlyaVarelas XaralabosCisse Ibrahim I.Sherman Michael Y.

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Hsp70-Bag3 complex is a hub for proteotoxicity-induced signaling that controls protein aggregation

机译：Hsp70-Bag3 complex is a hub for proteotoxicity-induced signaling that controls protein aggregation

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Protein abnormalities in cells are the cause of major pathologies, and a number of adaptive responses have evolved to relieve the toxicity of misfolded polypeptides. To trigger these responses, cells must detect the buildup of aberrant proteins which often associate with proteasome failure, but the sensing mechanism is poorly understood. Here we demonstrate that this mechanism involves the heat shock protein 70-Bcl-2-associated athanogene 3 (Hsp70-Bag3) complex, which upon proteasome suppression responds to the accumulation of defective ribosomal products, preferentially recognizing the stalled polypeptides. Components of the ribosome quality control system LTN1 and VCP and the ribosome-associated chaperone NAC are necessary for the interaction of these species with the Hsp70-Bag3 complex. This complex regulates important signaling pathways, including the Hippo pathway effectors LATS1/2 and the p38 and JNK stress kinases. Furthermore, under proteotoxic stress Hsp70-Bag3-LATS1/2 signaling regulates protein aggregation. We established that the regulated step was the emergence and growth of abnormal protein oligomers containing only a few molecules, indicating that aggregation is regulated at very early stages. The Hsp70-Bag3 complex therefore functions as an important signaling node that senses proteo-toxicity and triggers multiple pathways that control cell physiology, including activation of protein aggregation.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2018年第30期|E7043-E7052|共10页
作者
Meriin Anatoli B.; Narayanan Arjun; Meng LeAlexandrov IlyaVarelas XaralabosCisse Ibrahim I.Sherman Michael Y.;
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作者单位

MIT, Dept Phys, Cambridge, MA 02139 USA;

Ariel Univ, Dept Mol Biol, IL-40700 Ariel, Israel;

Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USAActivSignal, Watertown, MA 02471 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
proteasome inhibition; DRiPs; aggresome; Hippo pathway; stress kinases;

Hsp70-Bag3 complex is a hub for proteotoxicity-induced signaling that controls protein aggregation

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