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.
Authors
Juan Rivera-Correa, Sanjay Gupta, Edd Ricker, Danny Flores-Castro, Daniel Jenkins, Stephen Vulcano, Swati P. Phalke, Tania Pannellini, Matthew M. Miele, Zhuoning Li, Nahuel Zamponi, Young-Bum Kim, Yurii Chinenov, Eugenia Giannopoulou, Leandro Cerchietti, Alessandra B. Pernis
Figure 6
ROCK1 limits the assembly of p62 complexes enriched in mTORC1, ripoptosome components, and ALS-linked molecules.
