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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2018-07, Vol.115 (30), p.E7043-E7052
• Main Authors: Meriin, Anatoli B., Narayanan, Arjun, Meng, Le, Alexandrov, Ilya, Varelas, Xaralabos, Cissé, Ibrahim I., Sherman, Michael Y.
• Format: Article
• Language: English
• Subjects: Abnormalities; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Agglomeration; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2 protein; Biological Sciences; Cell activation; Heat shock proteins; HeLa Cells; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Humans; Kinases; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Oligomers; PNAS Plus; Polypeptides; Proteasomes; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - metabolism; Protein Aggregation, Pathological - pathology; Protein interaction; Proteins; Proteostasis Deficiencies - genetics; Proteostasis Deficiencies - metabolism; Proteostasis Deficiencies - pathology; Quality control; Signal Transduction; Signaling; Toxicity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1803130115

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.