PT  - JOURNAL ARTICLE
AU  - Inah Hwang
AU  - Ziwei Dai
AU  - Fei Li
AU  - Teresa Sanchez
AU  - Jason W Locasale
AU  - Lewis L Cantley
AU  - Hongwu Zheng
AU  - Jihye Paik
TI  - Cellular Stress Signaling Activates Type-I IFN Response Through FOXO3-regulated Lamin Posttranslational Modification
AID  - 10.1101/2020.05.03.075143
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.03.075143
4099  - http://biorxiv.org/content/early/2020/05/04/2020.05.03.075143.short
4100  - http://biorxiv.org/content/early/2020/05/04/2020.05.03.075143.full
AB  - Neural stem/progenitor cells (NSPCs) persist over the lifespan while encountering constant challenges from age or injury related brain environmental changes, including elevated oxidative stress. A time-dependent stress response that regulates the dynamic balance between quiescence and differentiation is thus essential to preserve NSPC long-term regenerative potential. Here we report that acutely elevated cellular oxidative stress in NSPCs suppresses neurogenic differentiation through induction of FOXO3-mediated cGAS/STING and type I interferon (IFN-I) responses. We show that oxidative stress activates FOXO3 promoting upregulation of its transcriptional target glycine-N-methyltransferase (GNMT) and thus 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 trigger cytosolic release of chromatin fragments and subsequent activation of the cGAS/STING/IFN-I cascade. Together, our findings suggest the FOXO3-GNMT/SAM-lamin-cGAS/STING-IFN-I signaling cascade as a critical stress response program that preserves its long-term regenerative potential.Competing Interest StatementLCC is a founder and member of the BOD of Agios Pharmaceuticals and is a founder and receives research support from Petra Pharmaceuticals. These companies are developing novel therapies for cancer. Other authors have declared that no conflict of interest exists.