{"doi":"10.1016/j.isci.2022.104282","title":"Cytoplasmic proteotoxicity regulates HRI-dependent phosphorylation of eIF2α via the Hsp70-Bag3 module","abstract":"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.","journal":"iScience","year":2022,"id":265765,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":825743,"name":"Santosh Kumar","orcid":"0000-0003-1744-337X","position":1,"is_corresponding":false},{"id":752816,"name":"Simone Baldan","orcid":null,"position":2,"is_corresponding":false},{"id":825744,"name":"Arkadi Hesin","orcid":"0000-0001-5841-5469","position":3,"is_corresponding":false},{"id":752817,"name":"Julia A. Yaglom","orcid":null,"position":4,"is_corresponding":false},{"id":752159,"name":"Michael Y. Sherman","orcid":"0000-0001-7392-320X","position":5,"is_corresponding":false},{"id":825742,"name":"Shivani Patel","orcid":"0000-0003-0906-2841","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:26:49.862989Z","pmid":"35573186","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}