# The role of UFMylation in ribosome quality control at the ER

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $582,648

## Abstract

Project Summary
Ribosomes are macromolecular machines that decode the genome. Quality control
mechanisms that ensure the fidelity of this process are thus of paramount importance cellular
and organismal viability. Ribosomes move at variable rates, slowing down or even pausing to
facilitate organelle targeting, domain folding and co-translational assembly, but prolonged stalls
are deleterious to cells because they can deplete functional ribosomes and produce highly toxic
truncated nascent chains. Stalls that occur on endoplasmic reticulum (ER) ribosomes are even
more damaging because they additionally obstruct the translocons through which all secreted
and membrane proteins must transit en route to the secretory pathway. Ribosome quality
control (RQC) is a conserved and essential process that rescues stalled 60S subunits by
extracting the obstructing nascent chain and degrading it by the UPS. Despite immense
progress in the past decade in defining RQC for cytosolic ribosome, the how RQC operates for
ER-stalled ribosomes is almost completely uninvestigated. Recently my lab discovered that
UFMylation – the process by which UFM1, a small ubiquitin-like protein is conjugated to
ribosomes — plays a central and essential role specifically in adapting RQC to proteins
synthesized at the ER. The three specific aims described in this proposal seek to build on the
foundation provided by our extensive preliminary data to define the mechanism by which
nascent chains that obstruct ribosomes that stall on ER translocons are extracted and
degraded. In aim 1 we will conduct a systematic dissection of the RQC machinery to define the
role of known RQC required to resolve stalled ribosomes at the ER. In aim 2 we will define the
interplay between ribosome UFMylation and RQC and dentify the readers of UFMylated
ribosomes at the ER. In aim 3 we will determine the structure of UFMyulated ribosomes and the
E3 ligase that conjugates UFM1 to the ribosome.

## Key facts

- **NIH application ID:** 10757419
- **Project number:** 5R01GM148477-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** RON R KOPITO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $582,648
- **Award type:** 5
- **Project period:** 2023-01-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757419

## Citation

> US National Institutes of Health, RePORTER application 10757419, The role of UFMylation in ribosome quality control at the ER (5R01GM148477-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10757419. Licensed CC0.

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