Non-Canonical Caspase Activity Antagonizes p38 MAPK Stress-Priming Function to Support Development

Dev Cell. 2020 May 4;53(3):358-369.e6. doi: 10.1016/j.devcel.2020.03.015. Epub 2020 Apr 16.

Abstract

Recent studies have revealed non-canonical activities of apoptotic caspases involving specific modulation of gene expression, such as limiting asymmetric divisions of stem-like cell types. Here we report that CED-3 caspase negatively regulates an epidermal p38 stress-responsive MAPK pathway to promote larval development in C. elegans. We show that PMK-1 (p38 MAPK) primes animals for encounters with hostile environments at the expense of retarding post-embryonic development. CED-3 counters this function by directly cleaving PMK-1 to promote development. Moreover, we found that CED-3 and PMK-1 oppose each other to balance developmental and stress-responsive gene expression programs. Specifically, expression of more than 300 genes is inversely regulated by CED-3 and PMK-1. Analyses of these genes showed enrichment for epidermal stress-responsive factors, including the fatty acid synthase FASN-1, anti-microbial peptides, and genes involved in lethargus states. Our findings demonstrate a non-canonical role for a caspase in promoting development by limiting epidermal stress response programs.

Keywords: DUSP; NLP-29; VHP-1; innate immunity; kinase; metabolism; non-apoptotic; phosphatase; proteostasis; translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Caspases / genetics
  • Caspases / metabolism*
  • Gene Expression Regulation
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Proteolysis
  • Stress, Physiological*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Mitogen-Activated Protein Kinases
  • Pmk-1 protein, C elegans
  • p38 Mitogen-Activated Protein Kinases
  • Caspases
  • ced-3 protein, C elegans