Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification.

TitleCellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification.
Publication TypeJournal Article
Year of Publication2021
AuthorsHwang I, Uchida H, Dai Z, Li F, Sanchez T, Locasale JW, Cantley LC, Zheng H, Paik J
JournalNat Commun
Date Published2021 01 28
KeywordsAcetylcysteine, Animals, Cell Differentiation, Cells, Cultured, Forkhead Box Protein O3, Free Radical Scavengers, Glycine N-Methyltransferase, HEK293 Cells, Herbicides, Humans, Interferon Type I, Lamins, Mice, Neural Stem Cells, Oxidative Stress, Paraquat, Protein Processing, Post-Translational, S-Adenosylmethionine, Signal Transduction

Neural stem/progenitor cells (NSPCs) persist over the lifespan while encountering constant challenges from age or injury related brain environmental changes like elevated oxidative stress. But how oxidative stress regulates NSPC and its neurogenic differentiation is less clear. Here we report that acutely elevated cellular oxidative stress in NSPCs modulates neurogenic differentiation through induction of Forkhead box protein O3 (FOXO3)-mediated cGAS/STING and type I interferon (IFN-I) responses. We show that oxidative stress activates FOXO3 and its transcriptional target glycine-N-methyltransferase (GNMT) whose upregulation triggers depletion of s-adenosylmethionine (SAM), a key co-substrate involved in methyl group transfer reactions. Mechanistically, we demonstrate that reduced intracellular SAM availability disrupts carboxymethylation and maturation of nuclear lamin, which induce cytosolic release of chromatin fragments and subsequent activation of the cGAS/STING-IFN-I cascade to suppress neurogenic differentiation. Together, our findings suggest the FOXO3-GNMT/SAM-lamin-cGAS/STING-IFN-I signaling cascade as a critical stress response program that regulates long-term regenerative potential.

Alternate JournalNat Commun
PubMed ID33510167
PubMed Central IDPMC7843645
Grant ListR01 AG048284 / AG / NIA NIH HHS / United States
R01 NS114561 / NS / NINDS NIH HHS / United States
R56 AG048284 / AG / NIA NIH HHS / United States
Related Faculty: 
Hongwu Zheng, Ph.D. Ji-Hye Paik, Ph.D. Teresa Sanchez, Ph.D.

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