Serine mistranslation induces the integrated stress response without accumulation of uncharged tRNAs.

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that support robust and accurate protein synthesis. A rapidly expanding number of studies show that mutations in aaRSs lead to multiple human diseases, including neurological disorders and cancer. Much remains unknown about how aaRS mutations impact human health. In particular, how aminoacylation errors affect stress responses and fitness in eukaryotic cells remains poorly understood. The integrated stress response (ISR) is an adaptive mechanism in response to multiple stresses. However, chronic activation of the ISR contributes to the development of multiple diseases (e.g., neuropathies). Here we show that Ser misincorporation into Ala and Thr codons, resulting from aaRS editing defects or mutations in tRNAs, constitutively active the ISR. Such activation does not appear to depend on the accumulation of uncharged tRNAs, implicating that Ser mistranslation may lead to ribosome stalling and collision.