biostudies-literatureRivera-Correa JNIDDK NIH HHSNational Institute of HealthNCI NIH HHSNIAMS NIH HHSNIH HHSe180507https://www.ebi.ac.uk/biostudies/studies/S-EPMC11949073biostudies-literatureUnknown10(5)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 JCI insightROCK1 promotes B cell differentiation and proteostasis under stress through the heme-regulated proteins, BACH2 and HRI.PMC11949073P30 CA008748R01 DK129946R01AR078766,R01AI58579,R01DK129946,T32 AR071302,S10OD019986T32 AR071302R01 AR078766S10 OD019986Ricker EGupta SRivera-Correa JJenkins DPannellini TGiannopoulou EFlores-Castro DKim YBLi ZPhalke SPPernis ABZamponi NChinenov YCerchietti LMiele MMVulcano SfalseROCK1 promotes B cell differentiation and proteostasis under stress through the heme-regulated proteins, BACH2 and HRI.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 2025-01-01T00:00:00Z2025 Feb2026-06-02T07:21:02.043Z2025-06-28T03:05:27.13ZS-EPMC119490733990353210.1172/jci.insight.180507