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

• Published in: Nature communications 2021-03, Vol.12 (1), p.1484-1484, Article 1484
• Main Authors: Egge, Nathan, Arneaud, Sonja L. B., Fonseca, Rene Solano, Zuurbier, Kielen R., McClendon, Jacob, Douglas, Peter M.
• Format: Article
• Language: English
• Subjects: 13; 13/31; 13/89; 13/95; 14/19; 38/39; 49/61; 631/208; 631/337; 631/80; 64/11; 82/80; Adaptive systems; Animals; Animals, Genetically Modified; c-Jun protein; Caenorhabditis elegans - genetics; Caenorhabditis elegans - physiology; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Degeneration; Dual-Specificity Phosphatases - genetics; Dual-Specificity Phosphatases - metabolism; Endopeptidases - metabolism; Feedback loops; Gene Knockdown Techniques; Humanities and Social Sciences; Inactivation; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; MAP kinase; MAP Kinase Kinase Kinases - metabolism; MAP Kinase Signaling System; Mechanical stimuli; Mitogen-Activated Protein Kinase Kinases - metabolism; Molecular modelling; multidisciplinary; Nematodes; Nervous system; Neurodegeneration; Neurodegenerative Diseases - genetics; Phosphatase; Physical stress; Post-translation; Proteasomes; Proto-Oncogene Proteins c-jun - metabolism; Regulatory sequences; Science; Science (multidisciplinary); Signal Transduction; Stress, Mechanical; Transcription factors; Transcription Factors - metabolism; Transcriptome; Trauma
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21611-8

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. The nervous system utilizes adaptive strategies to mitigate trauma-induced neurodegeneration. Here, the authors report that a MAPK phosphatase VHP-1 is induced by trauma and regulates transcriptional responses to mechanical stress in a C. elegans model.