# “Regulation of Protein Quality Control by the VCP AAA-ATPase”

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2021 · $432,441

## Abstract

Project Abstract
Protein quality control is of critical importance in maintaining cellular protein homeostasis, especially during
stress, disease states and aging. These networks are comprised of: 1) chaperones that assist in protein folding
and stabilization of intermediates to prevent aggregation, and 2) degradation pathways, such as the ubiquitin
proteasome system and autophagy, to eliminate proteins and organelles with sub-optimal function. A decline in
protein quality control in aging cells contributes to the development of numerous genetically and clinically distinct
neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's, Parkinson's, Huntington's
and prion diseases. Valosin containing protein (VCP, also known as p97) is a AAA-ATPase that plays an
important role in the ubiquitin proteasome system to capture ubiquitylated substrates via designated adaptors to
mediate substrate degradation. Mutation of VCP causes several neurodegenerative disorders including ALS and
a rare multi-system disorder, inclusion body myopathy, Paget’s disease of the bone and frontotemporal dementia
(IBMPFD). The most commonly mutated region of VCP resides at the site of adaptor binding and in certain
instances these mutations alter the constellation of adaptors that are bound to VCP skewing its targeting to
substrates. A common cellular feature of VCP mutations is the formation and persistence of protein aggregates
that fail to be cleared. We have identified a specific VCP-adaptor complex that is targeted to the aggresome, a
structure that sequesters misfolded aggregated proteins formed during cell stress. While aggresomes are
generally cyto-protective, under conditions where they persist, for example in aging neurons with declining
protein quality control pathways, they eventually become cytotoxic. Depletion of the VCP adaptor leads to a
deficit in aggresome formation, stabilization of ubiquitylated substrates and triggers ER stress. We hypothesize
that VCP mediates aggresome clearance by adaptor specific targeting to enable clearance of specific misfolded
or aggregated substrates. We will use a combination of targeted molecular studies, quantitative proteomics and
high-resolution imaging to achieve the main objectives of this proposal. We will (1) characterize the VCP
aggresome targeted complex to determine mechanisms of targeting and its functions within the aggresome (2)
identify ubiquitylated cellular targets of the VCP complex targeted to the aggresome using ubiquitin remnant
capture proteomics and (3) determine whether disease-relevant VCP mutations impact its association with the
aggresome complex and test if the VCP adaptor can recognize and enable clearance of disease relevant protein
aggregates. Successful implementation of this proposal will identify new targets that can be pursued for the
development of agents that enable aggregate clearance in a number of neurodegenerative disorders.

## Key facts

- **NIH application ID:** 10136010
- **Project number:** 5R01GM127557-04
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Malavika Raman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $432,441
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136010

## Citation

> US National Institutes of Health, RePORTER application 10136010, “Regulation of Protein Quality Control by the VCP AAA-ATPase” (5R01GM127557-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10136010. Licensed CC0.

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