Unmasking p38 MAPK Functions in Lysosome Homeostasis during Development and Aging

Project Summary Compromised tissue integrity is a major cause of debility during aging. Emerging findings suggest critical functions of lysosomes promoting tissue integrity. Our unpublished findings indicate key roles for C. elegans PMK-1, a conserved p38 MAPK member, in promoting lysosome formation and tissue integrity during

development and aging. These non-cell autonomous functions signal between germline, epidermis and nerve. Moreover, our data indicate that p38 MAPK acts on distinct targets in a tissue-specific and stage- specific manner to promote lysosome function. It is not known how p38 MAPK signals between tissues to

coordinate lysosome function. We hypothesize that PMK-1 promotes lysosome function by signaling a cell non-autonomous network regulating the regeneration and heterogeneity of lysosomes across tissues. Over the next 2-years, the critical goals for this project are to: 1) define the PMK-1 interactome required for

lysosome regeneration, 2) reveal tissue and stage-specific functions of PMK-1 in lysosome regeneration and heterogeneity, and 3) delineate tissue-specific contributions to PMK-1 cross-tissue signaling. We have built an array of tools to deeply understand how p38 signaling regulates lysosome regeneration and

heterogeneity to promote tissue integrity. Our proposed interdisciplinary studies include proteomics, genetic screens, biochemical analyses, and cell biology approaches to tackle this complex problem of understanding non-cell autonomous p38 MAPK function. The long-term objective of the proposed studies is

to understand the molecular and physiological mechanisms of p38 MAPK signaling in tissue integrity during development and aging.