Modulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging
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Abstract
The conserved p38 MAPK family is activated by phosphorylation during stress responses and inactivated by phosphatases. C. elegans PMK-1 p38 MAPK initiates innate immune responses and blocks development when hyperactivated. Here we show that PMK-1 signaling is enhanced during early aging by modulating the stoichiometry of non-phospho-PMK-1 to promote tissue integrity and longevity. Loss of pmk-1 function accelerates progressive declines in neuronal integrity and lysosome function compromising longevity which has both cell autonomous and cell non-autonomous contributions. CED-3 caspase cleavage limits phosphorylated PMK-1. Enhancing p38 signaling with caspase cleavage-resistant PMK-1 protects lysosomal and neuronal integrity extending a youthful phase. PMK-1 works through a complex transcriptional program to regulate lysosome formation. During early aging, the absolute phospho-p38 amount is maintained but the reservoir of non-phospho-p38 diminishes to enhance signaling without hyperactivation. Our findings show that modulating the stoichiometry of non-phospho-p38 dynamically supports tissue-homeostasis during aging without hyper-activation of stress response.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice
Holzenberger, M., Dupont, J., Ducos, B., Leneuve, P., Géloën, A., Even, P. C., Cervera, P., & Le Bouc, Y. (2003) · Nature · doi:10.1038/nature01298 · Cited by 2,109 · see citing works
Ageing as a Risk Factor for Disease
Niccoli, T., & Partridge, L. (2012) · Current Biology · doi:10.1016/j.cub.2012.07.024 · Cited by 1,831 · see citing works
The Biology of Proteostasis in Aging and Disease
Labbadia, J., & Morimoto, R. I. (2015) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060614-033955 · Cited by 1,472 · see citing works
Differential regulation and properties of MAPKs
Raman, M., Chen, W., & Cobb, M. H. (2007) · Oncogene · doi:10.1038/sj.onc.1210392 · Cited by 1,430 · see citing works
Self-citationSignaling networks determining life span
Riera, C. E., Merkwirth, C., De Magalhaes Filho, C. D., & Dillin, A. (2016) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060815-014451 · Cited by 161 · see citing works
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- Authors
- Yuan, W., Weaver, Y. M., Earnest, S., Taylor, C. A., Cobb, M. H., & Weaver, B. P.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Weaver, Benjamin P.
- Venue
- Nature Communications
- Published
- 2023-07-28
- Volume
- 14
- Issue
- 1
- Pages
- 4543-4543
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10382525
- OpenAlex
- W4385347917
- Cited by
- 56
- References
- 6
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 25
- FWCI
- 4.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- 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
- Welch Foundation (I-2022-20190330, I1243)
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35GM133755)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- p38 MAPK, pmk-1, proteostasis, aging, longevity, tissue integrity, lysosomal function, neuronal integrity, transcriptional regulation, Caenorhabditis elegans, innate immunity, stress response
- MeSH terms
- Proteostasis, Aging, Animals, Caenorhabditis elegans, Caspases, Mitogen-Activated Protein Kinases, Caenorhabditis elegans Proteins, p38 Mitogen-Activated Protein Kinases
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