{"doi":"10.1172/jci.insight.180507","title":"ROCK1 promotes B cell differentiation and proteostasis under stress through the heme-regulated proteins, BACH2 and HRI","abstract":"The mechanisms utilized by differentiating B cells to withstand highly damaging conditions generated during severe infections, like the massive hemolysis that accompanies malaria, are poorly understood. Here, we demonstrate that ROCK1 regulates B cell differentiation in hostile environments replete with pathogen-associated molecular patterns (PAMPs) and high levels of heme by controlling 2 key heme-regulated molecules, BACH2 and heme-regulated eIF2α kinase (HRI). ROCK1 phosphorylates BACH2 and protects it from heme-driven degradation. As B cells differentiate, furthermore, ROCK1 restrains their pro-inflammatory potential and helps them handle the heightened stress imparted by the presence of PAMPs and heme by controlling HRI, a key regulator of the integrated stress response and cytosolic proteotoxicity. ROCK1 controls the interplay of HRI with HSP90 and limits the recruitment of HRI and HSP90 to unique p62/SQSTM1 complexes that also contain critical kinases like mTOR complex 1 and TBK1, and proteins involved in RNA metabolism, oxidative damage, and proteostasis like TDP-43. Thus, ROCK1 helps B cells cope with intense pathogen-driven destruction by coordinating the activity of key controllers of B cell differentiation and stress responses. These ROCK1-dependent mechanisms may be widely employed by cells to handle severe environmental stresses, and these findings may be relevant for immune-mediated and age-related neurodegenerative disorders.","journal":"JCI Insight","year":2025,"id":551494,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":420515,"name":"Sanjay Gupta","orcid":"0000-0003-1714-3895","position":1,"is_corresponding":false},{"id":420513,"name":"Edd Ricker","orcid":"0000-0001-8779-1105","position":2,"is_corresponding":false},{"id":476283,"name":"Danny Flores-Castro","orcid":null,"position":3,"is_corresponding":false},{"id":634534,"name":"Daniel E. Jenkins","orcid":"0000-0002-6118-5411","position":4,"is_corresponding":false},{"id":1189122,"name":"Stephen Vulcano","orcid":"0009-0009-2001-9650","position":5,"is_corresponding":false},{"id":853327,"name":"Swati Phalke","orcid":"0000-0002-9061-0931","position":6,"is_corresponding":false},{"id":383407,"name":"Tania Pannellini","orcid":"0000-0002-0224-9921","position":7,"is_corresponding":false},{"id":284894,"name":"Matthew M. Miele","orcid":"0000-0001-7495-2133","position":8,"is_corresponding":false},{"id":618828,"name":"Zhuoning Li","orcid":"0009-0005-9064-8170","position":9,"is_corresponding":false},{"id":574494,"name":"Nahuel Zamponi","orcid":"0000-0002-9596-1095","position":10,"is_corresponding":false},{"id":298024,"name":"Young‐Bum Kim","orcid":"0000-0001-9471-6330","position":11,"is_corresponding":false},{"id":334718,"name":"Yurii Chinenov","orcid":"0000-0001-5226-8541","position":12,"is_corresponding":false},{"id":647232,"name":"Ευγενία Γιαννοπούλου","orcid":null,"position":13,"is_corresponding":false},{"id":237480,"name":"Leandro Cerchietti","orcid":"0000-0003-0608-1350","position":14,"is_corresponding":false},{"id":420518,"name":"Alessandra B. Pernis","orcid":"0000-0001-8259-1446","position":15,"is_corresponding":false},{"id":506354,"name":"Juan Rivera‐Correa","orcid":"0000-0003-4822-0005","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T02:54:25.065895Z","pmid":"39903532","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":[]}