Regulation of Stress Granule Dynamicity by Valosin‐Containing Protein

Abstract

Stress granules are dynamic biomolecular condensates of proteins and non‐translating RNAs that form when translation is inhibited during stress. Stress conditions associated with disease including ER dysfunction, toxic metalloids, and inflammatory factors induce stress granule formation. Stress granules disassemble when translation resumes during the recovery from stress. Aberrant, cytotoxic stress granules are implicated in degenerative diseases of the nervous, muscular and skeletal systems. Yet, the mechanisms underlying stress granule dynamicity are not well understood. A growing body of research suggests that the ubiquitin‐proteasome system regulates the formation and disassembly of stress granules. Valosin‐containing protein (VCP) is a homohexameric AAA+ ATPase that functions as a ubiquitin‐binding protein segregase in protein quality control and general protein degradation pathways in the ubiquitin‐proteasome system. Prior research demonstrated that VCP is an important mediator of stress granule disassembly. Our recent work suggests an additional role for VCP in stress granule assembly. By imaging single mRNA molecules in living and fixed human cells, we determined that VCP and other members of the ribosome‐associated quality control pathway (i.e. listerin, nuclear export mediator factor, and the proteasome) are critical for the release of specific mRNAs from translation complexes and localization to stress granules. Overexpression of VCP alleles associated with amyotrophic lateral sclerosis and frontotemporal dementia caused increased mRNA localization to stress granules. Thus, understanding the molecular mechanisms by which VCP regulates stress granules will be important for discovering its role in disease. This research will contribute to our knowledge of how defects in stress granules and the ubiquitin‐proteasome system drive human degenerative diseases and suggest potential diagnostic and therapeutic strategies.