Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification
Open accessPublished version of a preprint
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
FOXO factors are also activated by oxidative stress and can induce interferon production in NSCs via the STING pathway.
“FOXO factors are also activated by oxidative stress and can induce interferon production in NSCs via the STING pathway93.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [93]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 78 · Cited by 61
- Authors
- Hwang, I., Uchida, H., Dai, Z., Li, F., Sanchez, T., Locasale, J. W., Cantley, L. C., Zheng, H., & Paik, J.
- Affiliations
- Weill Cornell Medicine (US)
- Duke University (US)
- Southwest Hospital (CN)
- NewYork–Presbyterian Hospital (US)
- Corresponding author
- Paik, Jihye
- ORCID
- Venue
- Nature Communications
- Published
- 2021-01-28
- Volume
- 12
- Issue
- 1
- Pages
- 640-640
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7843645
- OpenAlex
- W3124129117
- Cited by
- 61
- References
- 78
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 12 · 2023: 10 · 2022: 8 · 2021: 2 · 2020: 1
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG048284)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- oxidative stress, neural stem/progenitor cells, neurogenic differentiation, FOXO3, type I interferon, cGAS-STING, glycine N-methyltransferase, S-adenosylmethionine, nuclear lamins, chromatin release, cellular stress signaling, brain regeneration
- MeSH terms
- Forkhead Box Protein O3, Acetylcysteine, Animals, Cell Differentiation, Cells, Cultured, Herbicides, Humans, Interferon Type I, Paraquat, Protein Processing, Post-Translational, S-Adenosylmethionine, Signal Transduction, Free Radical Scavengers, Oxidative Stress, Lamins, Glycine N-Methyltransferase, Mice, HEK293 Cells, Neural Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
