PERK crosstalk between ER and microtubule dynamics

The architecture of the endoplasmic reticulum (ER) is tightly controlled as a key determinant of its function. Its dynamics are linked to those of the cytoskeleton, but our understanding of how this coordination occurs and what its functional relevance is, is limited. We found the Unfolded Protein Response (UPR) transducer EIF2AK3/PERK is essential for acute stress-induced peripheral redistribution and remodeling of the ER, through eIF2a phosphorylation and translation initiation shutdown. PERK-mediated eIF2a phosphorylation can be bypassed by blocking polysome assembly; by depleting microtubule-anchoring ER proteins such as REEP4, p180/RRBP1 and Climp63/CKAP4; or by disrupting the microtubule cytoskeleton. Notably, specific disruption of non-centrosomal microtubules, but not centrosome depletion, relieved blockade of ER redistribution in PERK-deficient cells. Conversely, PERK deficiency stabilized non-centrosomal microtubules promoting polarized protrusiveness in epithelial cells and neuroblasts. Thus, PERK coordinates ER architecture and homeostasis with cell morphogenesis by coupling ER remodeling and non-centrosomal MT stability and dynamics.