Nonmuscle Myosin IIB Links Cytoskeleton to IRE1α Signaling during ER Stress

Here we identify and characterize a cytoskeletal myosin protein required for IRE1 alpha oligomerization, activation, and signaling. Proteomic screening identified nonmuscle myosin heavy chain IIB (NMHCIIB), a subunit of nonmuscle myosin IIB (NMIIB), as an ER stress-dependent interacting protein specific to IRE1 alpha. Loss of NMIIB compromises XBP1s and UPR target gene expression with no effect on the PERK pathway. Mechanistically, NMIIB is required for IRE1 alpha aggregation and foci formation under ER stress. The NMIIB-mediated effect on IRE1 alpha signaling is in part dependent on the phosphorylation of myosin regulatory light chain and the actomyosin contractility of NMIIB. Biologically, the function of NMIIB in ER stress response is conserved as both mammalian cells and C. elegans lacking NMIIB exhibit hypersensitivity to ER stress. Thus, optimal IRE1 alpha activation and signaling require concerted coordination between the ER and cytoskeleton.