# Leveraging ubiquitin-dependent regulatory mechanisms to improve proteome quality in health and disease

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $324,295

## Abstract

PROJECT SUMMARY
Errors associated with DNA replication, transcription, mRNA processing, and protein biogenesis result in the
continuous production of potentially toxic defective proteins. The error-prone nature of these essential processes
requires robust quality control (QC) systems to effectively triage and destroy defective translation products.
Protein quality control is an essential component within the larger protein homeostasis (proteostasis) system and
proteostasis dysfunction has been implicated in human aging-related pathologies. On one hand, elevated protein
QC function is needed to enable neoplastic cell proliferation in cells with high mutational burdens or chromosomal
abnormalities. Conversely, impaired proteostasis and defects in protein QC function result in the enhanced
production of misfolded and toxic aggregation prone proteins that typify many neurodegenerative disorders.
These observations suggest that developing molecular strategies to predictably alter QC function to either
enhance, or limit QC capacity as needed can improve aging-associated disorders and extend human healthspan.
However, there is a surprising and substantial gap in our understanding of not only how QC systems selectively
engage their substrates, but also how substrates evade detection during proteostasis dysfunction. To make
substantive progress toward the goal of leveraging QC systems to combat aging-associated disorders, it is
necessary to identify and characterize cellular and molecular mechanisms that enable detection and degradation
of diverse QC substrates. Recent research progress from my lab has identified a spatially restricted QC pathway
that acts on stalled and collided ribosomal complexes both before and after translation initiation to target
defective translation products for degradation and recycle ribosomal complexes. Further, we have developed a
systematic pipeline for biochemical, structural, and cellular interrogation of enigmatic but critical QC ubiquitin
ligases that have been implicated in targeting diverse substrates for degradation by unknown mechanisms. We
have focused our initial studies on the ubiquitin ligase HUWE1. Our recently described HUWE1 structure
represents the first full-length structure of a HECT-domain ligase. We have generated a unique and powerful set
of genome-edited cell lines and HUWE1 variants that have and will enable molecular dissection of HUWE1
function, HUWE1 substrate identification, and identification of cellular stress conditions that require HUWE1 for
cellular survival and proliferation. Research outcomes achieved by the proposed studies will mechanistically
determine how terminally stalled ribosomes are sensed and resolved and how ribosome-associated QC
pathways can be manipulated to alter proteostasis function. Further, we will establish mechanisms by which QC
ligases engage substrates under normal and stressed conditions. Successful completion of the proposed
research will provide substantial progress...

## Key facts

- **NIH application ID:** 10552479
- **Project number:** 1R35GM148339-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Eric J Bennett
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $324,295
- **Award type:** 1
- **Project period:** 2023-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10552479

## Citation

> US National Institutes of Health, RePORTER application 10552479, Leveraging ubiquitin-dependent regulatory mechanisms to improve proteome quality in health and disease (1R35GM148339-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10552479. Licensed CC0.

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