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.

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

“…The depletion of SYNPO2 releases BAG3 from its autophagic roles and upregulates YAP/TAZ-mediated transcription [466]. It was recently reported that the BAG3-HSPA complex is critical in the LATS1/2-mediated phosphorylation of YAP, which is indicative of Hippo pathway activation [487].…”

Dysregulated interactions triggered by a neuropathy-causing mutation in the IPV motif of HSP27

“…Moreover, BAG3 is recruited to stress granules via its interactions with HSPB8 where the BAG3-HSP8-HSP70 complex plays a key role in ensuring stress granule functionality (77). Disturbing the dynamic balance of the HSP27-BAG3 interaction might therefore affect a wider chaperone network and contribute to destabilization of proteostasis (78). Notably, mutations in the BAG3 IPV motifs also contribute to human disease: a Pro-to-Leu mutation is implicated in myofibrillar myopathy (34, 75, 79) and another Pro-to-Ser mutation is implicated in CMT disease (80).…”

BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes

“…This suggests that the aggresomes are not formed in response to an overload of ubiquitinylated proteins. Whether the aggregation of BAG3 itself is the underlying cue to form aggresomes remains unclear since BAG3 was also shown to regulate aggresome formation through the Hippo pathway (Meriin et al 2018). So aberrant activation of the Hippo pathway may also explain the formation of aggresomes.…”

“…For instance, the BAG-domain is known to mediate the interaction with Hsp70/Hsc70 or Bcl2 (Takayama et al 1995(Takayama et al , 1997(Takayama et al and 1999. The IPV-motifs have been shown to be indispensable for binding to small heat shock proteins (sHSPs) (Fuchs et al 2010), the WW-domain binds LATS1 (Meriin et al 2018), and the PxxP domain is necessary for the interaction with dynein and PLC-γ (Doong et al 2000, Gamerdinger et al 2011).…”