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 and Jihye Paik ()
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Inah Hwang: Weil Cornell Medicine
Hiroki Uchida: Weil Cornell Medicine
Ziwei Dai: Duke University School of Medicine
Fei Li: Southwest Hospital
Teresa Sanchez: Weil Cornell Medicine
Jason W. Locasale: Duke University School of Medicine
Lewis C. Cantley: Weil Cornell Medicine
Hongwu Zheng: Weil Cornell Medicine
Jihye Paik: Weil Cornell Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20839-0

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