RT Journal Article SR Electronic T1 Translation rescue by targeting Ppp1r15a upstream open reading frame in vivo JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.12.11.472232 DO 10.1101/2021.12.11.472232 A1 Ashley Kidwell A1 Shiv Pratap Singh Yadav A1 Bernhard Maier A1 Amy Zollman A1 Kevin Ni A1 Arvin Halim A1 Danielle Janosevic A1 Jered Myslinski A1 Farooq Syed A1 Lifan Zeng A1 Alain Bopda Waffo A1 Kimihiko Banno A1 Xiaoling Xuei A1 Emma H. Doud A1 Pierre C. Dagher A1 Takashi Hato YR 2021 UL http://biorxiv.org/content/early/2021/12/12/2021.12.11.472232.abstract AB The eIF2 initiation complex is central to maintaining a functional translation machinery. Extreme stress such as life-threatening sepsis exposes vulnerabilities in this tightly regulated system, resulting in an imbalance between the opposing actions of kinases and phosphatases on the main regulatory subunit eIF2α. Here, we report that translation shutdown is a hallmark of established sepsis-induced kidney injury brought about by excessive eIF2α phosphorylation and sustained by blunted expression of the counterregulatory phosphatase subunit Ppp1r15a. We determined that the blunted Ppp1r15a expression persists because of the presence of an upstream open reading frame (uORF). Overcoming this barrier with genetic approaches enabled the derepression of Ppp1r15a, salvaged translation and improved kidney function in an endotoxemia model. We also found that the loss of this uORF has broad effects on the composition and phosphorylation status of the immunopeptidome that extended beyond the eIF2α axis. Collectively, our findings define the breath and potency of the highly conserved Ppp1r15a uORF and provide a paradigm for the design of uORF-based translation rheostat strategies. The ability to accurately control the dynamics of translation during sepsis will open new paths for the development of therapies at codon level precision.Competing Interest StatementThe authors have declared no competing interest.