Cytoplasmic proteotoxicity regulates HRI-dependent phosphorylation of eIF2α via the Hsp70-Bag3 module

Shivani Patel, Santosh Kumar, Simone Baldan, Arkadi Hesin, Julia Yaglom, Michael Y. Sherman

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


The major heat shock protein Hsp70 forms a complex with a scaffold protein Bag3 that links it to components of signaling pathways. Via these interactions, the Hsp70-Bag3 module functions as a proteotoxicity sensor that controls cell signaling. Here, to search for pathways regulated by the complex, we utilized JG-98, an allosteric inhibitor of Hsp70 that blocks its interaction with Bag3. RNAseq followed by the pathway analysis indicated that several signaling pathways including UPR were activated by JG-98. Surprisingly, only the eIF2α-associated branch of the UPR was activated, while other UPR branches were not induced, suggesting that the response was unrelated to the ER proteotoxicity and ER-associated kinase PERK1. Indeed, induction of the UPR genes under these conditions was driven by a distinct eIF2α kinase HRI. Hsp70-Bag3 directly interacted with HRI and regulated eIF2α phosphorylation upon cytoplasmic proteotoxicity. Therefore, cytosolic proteotoxicity can activate certain UPR genes via Hsp70-Bag3-HRI-eIF2α axis.

Original languageEnglish
Article number104282
Issue number5
StatePublished - 20 May 2022


  • Molecular biology
  • Molecular interaction
  • Protein


Dive into the research topics of 'Cytoplasmic proteotoxicity regulates HRI-dependent phosphorylation of eIF2α via the Hsp70-Bag3 module'. Together they form a unique fingerprint.

Cite this