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

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

doi:10.1038/s41467-020-20839-0

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.

Highlights

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
There still lacks a mechanistic understanding of how oxidative stress affects Forkhead box protein O (FOXO) activation systematically and whether and how that contributes to the neuroprotective responses
Compared to the mock-treated control NSPCs, we found that NSPCs under PQ but not NAC treatment, exhibited marked reduction in their production of TUBB3positive newly born neurons when induced to differentiate (Fig. 1c), suggesting a regulatory role of oxidative stress response on neurogenic differentiation

Summary

Introduction

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. Previous studies found that FOXO expression in the central nervous system serves a key role in preserving neural stem cell pools[9,10], it protects neurons against agerelated axonal degeneration across species[16,17,18] Despite these revelations, there still lacks a mechanistic understanding of how oxidative stress affects FOXO activation systematically and whether and how that contributes to the neuroprotective responses. Using NSPCs as a system, we further demonstrated that reduction of intracellular SAM availability compromises nuclear lamin maturation that would eventually lead to cytosolic DNA leakage, cGAS/STING activation, and IFN-I response to suppress neurogenic differentiation. These findings established FOXO3-GNMT/SAMlamin-cGAS/STING-IFN-I signaling cascade as a critical stress response program that regulates NSPC differentiation

Methods

Results

Conclusion