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

Anatoli B. Meriin, Arjun Narayanan, Le Meng, Ilya Alexandrov, Xaralabos Varelas, Ibrahim I. Cissé, Michael Y. Sherman

Research output: Contribution to journalArticlepeer-review


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 oligo-mers 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.

Original languageEnglish (US)
Pages (from-to)E7043-E7052
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number30
StatePublished - Jul 24 2018


  • Aggresome
  • DRiPs
  • Hippo pathway
  • Proteasome inhibition
  • Stress kinases

ASJC Scopus subject areas

  • General


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