Plasticity of the mammalian integrated stress response.

ABSTRACT: An increased level of phosphorylation of eukaryotic translation initiation factor 2 subunit-α (eIF2α, encoded by EIF2S1; eIF2α-p) coupled with decreased guanine nucleotide exchange activity of eIF2B is a hallmark of the 'canonical' integrated stress response (c-ISR)¹. It is unclear whether impaired eIF2B activity in human diseases including leukodystrophies², which occurs in the absence of eIF2α-p induction, is synonymous with the c-ISR. Here we describe a mechanism triggered by decreased eIF2B activity, distinct from the c-ISR, which we term the split ISR (s-ISR). The s-ISR is characterized by translational and transcriptional programs that are different from those observed in the c-ISR. Opposite to the c-ISR, the s-ISR requires eIF4E-dependent translation of the ups

SUBMITTER: Chen CW 

PROVIDER: S-EPMC12119373 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature