# Ubiquitin Signaling

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $379,970

## Abstract

Project Summary
Ubiquitylation describes the process by which the small protein ubiquitin is covalently attached to other
proteins. Most, if not all, cellular processes are regulated in some way by ubiquitylation. Consequently,
defects in components of the ubiquitin system are associated with several human diseases, most notably
cancer and neurodegeneration. Over the past decade we have gained tremendous insight into the
molecular components and processes that conjugate ubiquitin to substrate proteins as well as the
subsequent degradation by the 26S proteasome. This knowledge stems primarily from studies of protein
degradation. Protein ubiquitylation has therefore become a synonym for a signal that induces proteolysis.
Surprisingly, comparative proteome-wide ubiquitin profiling experiments using proteasome inhibition
estimate that only about 60% of ubiquitylated proteins are efficiently degraded by the proteasome, implying
that protein ubiquitylation has widespread signaling functions independent of mediating proteolysis.
Despite the importance of ubiquitylation in biology and human health, and the apparent importance of non-
proteolytic functions of ubiquitylation, molecular concepts governing ubiquitin signaling are understudied
and our understanding remains rudimentary. However, detailed insight into processing of the diverse
ubiquitin signals will be important for basic biomedical research and development of therapeutics targeting
the ubiquitin system. Key questions are: Why are some ubiquitylated proteins degraded and others are
not? How can ubiquitylation directly affect protein activity? What is the role of different ubiquitin chain
topologies and posttranslational modifications on ubiquitin?
Over the past years we have developed a highly defined system that allows us to study these questions in
great detail. This system is focused on the cullin-RING ubiquitin ligase complex SCFMet30, which connects
metabolic or heavy metal stress to cell cycle regulation. SCFMet30 modifies a number of substrates with the
canonical degradation signal, the lysine-48 (K48) linked ubiquitin chain. Interestingly, while some
substrates behave as expected and are targeted for degradation by the 26S proteasome, other substrates
are regulated in a proteolysis-independent manner. This proposal builds on a plethora of tools we have
developed during past funding periods of this grant, which will allow us to analyze biochemistry and
physiology of ubiquitin signaling by addressing the following questions: (1) how is the critical change of the
ubiquitin chain topology from K48 to K11 achieved and how does it induce transcription factor activation;
(2) how does ubiquitylation trigger protein complex remodeling through recruitment of Cdc48/p97
complexes, (3) what are roles and mechanisms of the recently identified herterodimeric SCF complex with
the two essential F-box proteins Met30 and Cdc4 in restricting centromeric histone H3 incorporation; (4)
how do F-box proteins s...

## Key facts

- **NIH application ID:** 10072703
- **Project number:** 2R01GM066164-18
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Peter Kaiser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $379,970
- **Award type:** 2
- **Project period:** 2002-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072703

## Citation

> US National Institutes of Health, RePORTER application 10072703, Ubiquitin Signaling (2R01GM066164-18). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10072703. Licensed CC0.

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