부산대학교 도서관

Proteostasis is essential for cellular survival and particularly important for highly specialised post‐mitotic cells such as neurons. Transient reduction in protein synthesis by protein kinase R‐like endoplasmic reticulum (ER) kinase (PERK)‐mediated phosphorylation of eukaryotic translation initiation factor 2α (p‐eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type‐specific mechanisms that secure proteostatic stress resilience. Here, we demonstrate that PERK‐deficient neurons, unlike other cell types, fully retain the capacity to control translation during ER stress. We observe rescaling of the ATF4 response, while the reduction in protein synthesis is fully retained. We identify two molecular pathways that jointly drive translational control in PERK‐deficient neurons. Haem‐regulated inhibitor (HRI) mediates p‐eIF2α and the ATF4 response and is complemented by the tRNA cleaving RNase angiogenin (ANG) to reduce protein synthesis. Overall, our study elucidates an intricate back‐up mechanism to ascertain translational control during ER stress in neurons that provides a mechanistic explanation for the thus far unresolved observation of neuronal resilience to proteostatic stress. Synopsis: PERK‐mediated reduction of protein synthesis is an essential survival response during ER stress, yet neurons have been reported as tolerant to PERK dysregulation. Here PERK‐deficient neurons are found to possess an intricate cell‐type specific backup strategy to maintain translational control, which secures resilience to proteostatic stress. PERK‐deficient neurons retain the capacity to reduce protein synthesis during ER stress, whereas the ATF4 response is rescaled.Preservation of ER stress‐induced translational control is specific to neurons.The rescaled ER stress‐induced ATF4 response is fully p‐eIF2α‐dependent and mediated by HRI in PERK‐deficient neurons.An additional eIF2‐independent mechanism mediated by the tRNA cleaving RNase ANG preserves ER‐stress induced reduction of protein synthesis in absence of PERK. [ABSTRACT FROM AUTHOR]