Trauma-induced regulation of VHP-1 modulates the cellular response to mechanical stress

Nat Commun. 2021 Mar 5;12(1):1484. doi: 10.1038/s41467-021-21611-8.

Abstract

Mechanical stimuli initiate adaptive signal transduction pathways, yet exceeding the cellular capacity to withstand physical stress results in death. The molecular mechanisms underlying trauma-induced degeneration remain unclear. In the nematode C. elegans, we have developed a method to study cellular degeneration in response to mechanical stress caused by blunt force trauma. Herein, we report that physical injury activates the c-Jun kinase, KGB-1, which modulates response elements through the AP-1 transcriptional complex. Among these, we have identified a dual-specificity MAPK phosphatase, VHP-1, as a stress-inducible modulator of neurodegeneration. VHP-1 regulates the transcriptional response to mechanical stress and is itself attenuated by KGB-1-mediated inactivation of a deubiquitinase, MATH-33, and proteasomal degradation. Together, we describe an uncharacterized stress response pathway in C. elegans and identify transcriptional and post-translational components comprising a feedback loop on Jun kinase and phosphatase activity.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / metabolism*
  • Endopeptidases / metabolism
  • Gene Knockdown Techniques
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neurodegenerative Diseases / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • Signal Transduction
  • Stress, Mechanical*
  • Transcription Factors / metabolism
  • Transcriptome

Substances

  • Caenorhabditis elegans Proteins
  • JUN-1 protein, C elegans
  • Proto-Oncogene Proteins c-jun
  • Transcription Factors
  • JNK Mitogen-Activated Protein Kinases
  • KGB-1 protein, C elegans
  • DLK-1 protein, C elegans
  • MAP Kinase Kinase Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Dual-Specificity Phosphatases
  • VHP-1 protein, C elegans
  • Endopeptidases
  • MATH-33 protein, C elegans