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Published July 24, 2018 | Supplemental Material + Published
Journal Article Open

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

Abstract

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 proteotoxicity and triggers multiple pathways that control cell physiology, including activation of protein aggregation.

Additional Information

© 2018 The Author(s). Published under the PNAS license. Edited by Alfred Lewis Goldberg, Harvard Medical School, Boston, MA, and approved June 13, 2018 (received for review March 21, 2018) This work was supported by NIH Grant R01 CA176326 and NIH Clinical and Translational Science Institute Parental Award 1UL1TR001430 (to M.Y.S.). X.V. is supported by Department of Defense Congressionally Directed Medical Research Program Award W81XWH-14-1-0336 and NIH Grant R01 HL124392. Author contributions: A.B.M. and M.Y.S. designed research; A.B.M., A.N., and L.M. performed research; A.N., L.M., I.A., X.V., and I.I.C. contributed new reagents/analytic tools; A.B.M., A.N., L.M., X.V., I.I.C., and M.Y.S. analyzed data; and A.B.M. and M.Y.S. wrote the paper. Conflict of interest statement: I.A. is cofounder of ActivSignal. The authors declare no other conflicts of interest. This article is a PNAS Direct Submission. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1803130115/-/DCSupplemental.

Attached Files

Published - E7043.full.pdf

Supplemental Material - pnas.1803130115.sapp.pdf

Supplemental Material - pnas.1803130115.sd01.pdf

Supplemental Material - pnas.1803130115.sd02.pdf

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Created:
August 19, 2023
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