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bioRxiv · 10.1101/2022.07.12.499791

Balancing p38 MAPK Signaling with Proteostasis Mechanisms Supports Tissue Integrity during Aging in C. elegans

Yuan, W.·Weaver, Y. M.·Earnest, S.·Taylor, C. A.·Cobb, M. H.·Weaver, B. P.
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Abstract

Like other p38 MAPKs, C. elegans PMK-1 is activated by phosphorylation during stress responses and inactivated by phosphatases. PMK-1 initiates immune response and blocks development when hyperactivated. Here we show that PMK-1 signaling is essential for tissue homeostasis during aging. Loss of PMK-1 accelerates progressive declines in neuronal integrity and lysosome function compromising longevity. Enhancing p38 signaling with caspase cleavage-resistant PMK-1 protects lysosomal and neuronal integrity extending a youthful phase. The cleavage-resistant PMK-1 mutant behaves oppositely to the pmk-1 null in regulating both transcriptional and protein degradation programs supporting tissue homeostasis. PMK-1 activates a complex transcriptional program and requires UNC-62 (MEIS), FOS/JUN, and DAF-16 (FOXO) transcription factors to regulate lysosome formation which is both cell autonomous and non-cell autonomous. We show that during early aging the absolute phospho-p38 amount is nearly constant but maintained at a small percentage of total p38. The reservoir of non-phospho-p38 diminishes during early aging to enhance signaling without hyperactivation. CED-3 caspase cleavage limits phosphorylated PMK-1 and truncated PMK-1 is rapidly degraded by the proteasome. Modulating phospho-p38 ratio confers dynamic control for tissue-homeostasis without activating stress response to support longevity.

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Yuan, W., Weaver, Y. M., Earnest, S., Taylor, C. A., Cobb, M. H., Weaver, B. P.. 2022-07-13. Balancing p38 MAPK Signaling with Proteostasis Mechanisms Supports Tissue Integrity during Aging in C. elegans. https://doi.org/10.1101/2022.07.12.499791

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