# Mechanism and Function of Cotranslational Ubiquitylation

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $322,955

## Abstract

Project Summary/Abstract
 Protein quality control (QC) mechanisms exist in eukaryotic cells to monitor and clear misfolded,
damaged, or aggregated proteins, and defects in QC systems are recognized to be causative in several
disease states, particularly neurodegenerative disorders, cancer, cardiovascular, metabolic diseases,
aging. Many protein QC systems function at the earliest stages of the life of a protein, ensuring that
newly synthesized proteins reach a mature and functional state. While the ubiquitin-proteasome system
(UPS) has long been recognized to play an important role in protein QC, this was generally assumed to
occur after unsuccessful attempts at correctly folding newly synthesized proteins. In contrast, we made
the surprising discovery that ubiquitylation of nascent polypeptides also occurs within active translation
complexes, essentially marking proteins for destruction before their synthesis is even complete. Co-
translation ubiquitylation (CTU) is a surprisingly robust process in human cells, with approximately 10%
of nascent chains being ubiquitylated within active translation complexes. The incorporation of amino
acid analogs into nascent chains, as well as Hsp70 inhibitors, leads to sharp increases in CTU, strongly
suggesting that CTU reflects a protein QC pathway that targets aberrant or misfolded nascent
polypeptides. Importantly, CTU is distinct from ubiquitylation of nascent chains that occurs in the
context of defective and disassembled ribosome complexes (the “RQC” Ribosome Quality Control
pathway, dependent on the Ltn1 ubiquitin ligase). The goals of this proposal are to characterize the
CTU pathway with respect to the ubiquitin ligases, the targets, the factors that influence and potentially
regulate CTU, and to assess the biological importance of CTU. The specific aims are to 1) identify the
CTU ubiquitin ligases, in both yeast and human cells, through biochemical and genetic approaches, 2)
characterize the preferential targets of CTU by proteomic approaches in order to determine the features
of nascent polypeptides that are recognized by this QC system, and 3) determine the factors that
influence and regulate CTU. This will significantly impact our understanding of the relationship between
protein synthesis and protein quality control, with implications for disease states where proteostasis is
particularly critical.

## Key facts

- **NIH application ID:** 9978586
- **Project number:** 5R01GM103619-24
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** JON HUIBREGTSE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $322,955
- **Award type:** 5
- **Project period:** 1996-12-13 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978586

## Citation

> US National Institutes of Health, RePORTER application 9978586, Mechanism and Function of Cotranslational Ubiquitylation (5R01GM103619-24). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978586. Licensed CC0.

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