@article{da804242edf84ef08c63d401d0a33468,
title = "Modulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging",
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.",
author = "Wang Yuan and Weaver, {Yi M.} and Svetlana Earnest and Taylor, {Clinton A.} and Cobb, {Melanie H.} and Weaver, {Benjamin P.}",
note = "Funding Information: We thank David Mangelsdorf, Leon Avery, Duojia Pan, James Collins, Michael Reese, Matthew Sieber and David Corey for helpful discussions, the CGC (funded by NIH Office of Research Infrastructure Programs [P40 OD010440]) for materials; WormBase and UniProt databases. mRNA-seq was performed by the McDermott Center Sequencing Core and data analysis was provided by the McDermott Center Bioinformatics Lab. Protein mass-spectrometry was performed and analyzed by the UT Southwestern Proteomics Core facility. This work is supported by The Robert A. Welch Foundation grants I-2022-20190330 (BPW) and I1243 (MHC), and National Institutes of Health grant R35GM133755 (BPW). The funders had no role in study design, data acquisition, decision to publish, or preparation of the manuscript. Funding Information: We thank David Mangelsdorf, Leon Avery, Duojia Pan, James Collins, Michael Reese, Matthew Sieber and David Corey for helpful discussions, the CGC (funded by NIH Office of Research Infrastructure Programs [P40 OD010440]) for materials; WormBase and UniProt databases. mRNA-seq was performed by the McDermott Center Sequencing Core and data analysis was provided by the McDermott Center Bioinformatics Lab. Protein mass-spectrometry was performed and analyzed by the UT Southwestern Proteomics Core facility. This work is supported by The Robert A. Welch Foundation grants I-2022-20190330 (BPW) and I1243 (MHC), and National Institutes of Health grant R35GM133755 (BPW). The funders had no role in study design, data acquisition, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = dec,
doi = "10.1038/s41467-023-40317-7",
language = "English (US)",
volume = "14",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}