ROCK1 promotes B cell differentiation and proteostasis under stress through the heme-regulated proteins, BACH2 and HRI Journal Article
| Authors: | Rivera-Correa, J.; Gupta, S.; Ricker, E.; Flores-Castro, D.; Jenkins, D.; Vulcano, S.; Phalke, S. P.; Pannellini, T.; Miele, M. M.; Li, Z.; Zamponi, N.; Kim, Y. B.; Chinenov, Y.; Giannopoulou, E.; Cerchietti, L.; Pernis, A. B. |
| Article 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. © 2025, Rivera-Correa et al. |
| Journal Title: | JCI Insight |
| Volume: | 10 |
| Issue: | 5 |
| ISSN: | 2379-3708 |
| Publisher: | Amer Soc Clinical Investigation Inc |
| Date Published: | 2025-03-10 |
| Start Page: | e180507 |
| Language: | English |
| DOI: | 10.1172/jci.insight.180507 |
| PUBMED: | 39903532 |
| PROVIDER: | scopus |
| PMCID: | PMC11949073 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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