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

Inah Hwang, Hiroki Uchida, Ziwei Dai, Fei Li, Teresa Sanchez, Jason W. Locasale, Lewis C. Cantley, Hongwu Zheng, Jihye Paik

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish
Article number640
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - 1 Dec 2021

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© 2021, The Author(s).

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