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

Nathan Egge,Peter M Douglas,Kielen R Zuurbier,Jacob Mcclendon,Rene Solano Fonseca,Sonja L B Arneaud

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.

Highlights

Mechanical stimuli initiate adaptive signal transduction pathways, yet exceeding the cellular capacity to withstand physical stress results in death
We identify the mitogen-activated protein kinases (MAPKs) phosphatase, VHP-1, as a vital response element that negatively regulates its upstream Jun kinase, KGB-1, and itself is negatively regulated by stress-inactivation of a deubiquitinase, MATH-33
We have developed a multi-impact model of blunt force trauma in C. elegans utilizing high frequency, multidirectional agitation, which simultaneously delivers a rapid acceleration/deceleration injury to a large population of age-synchronized animals (Fig. 1a)

Summary

Introduction

Mechanical stimuli initiate adaptive signal transduction pathways, yet exceeding the cellular capacity to withstand physical stress results in death. Mechanotransduction, or the conversion of mechanical forces into chemical and electrical signals, enables cellular responsiveness to physical stimuli These include activation of several classes of protein kinases, small G-proteins, phospholipases, and direct signaling to the nucleus through the nesprin/SUN1 complex[3]. Activation of integrins[14,15], G protein-coupled receptors[16], and mechanosensitive cation channels[17] represent major mechanisms of mechanosensation These signaling events operate through several downstream pathways including calcium influx[18], protein kinase C (PKC)[19], mitogen-activated protein kinases (MAPKs), the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT)[20], focal adhesion kinase (FAK)[21], and several small GTPases including Ras, RhoA, and Rac[122,23]

Methods

Results

Conclusion