# Advancing Proteomics Technologies to Decipher the Ubiquitin-Proteasome System

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $266,283

## Abstract

Protein-protein interactions (PPIs) are key to the formation of protein complexes, the active components
responsible for a multitude of cellular functions. Aberrant PPIs can have detrimental effects on essential
biological processes and lead to various human diseases. Elucidating PPI networks and their structural features
within cells is central to understanding fundamental biology and molecular alterations associated with human
pathologies, and ultimately facilitating therapeutic development. However, delineation of proteome networks to
define the cell’s functional states at the systems-level is challenging due to limitations in existing approaches.
Cross-linking mass spectrometry (XL-MS) has emerged as a powerful technology for PPI studies, owing to its
unique capability of preserving and capturing protein interactions in their native environments, as well as
uncovering PPI identities with structural details. Although current XL-MS technologies are successful in global
PPI analysis, unmet challenges still remain especially for complete illustration and quantitative assessment of
cellular networks, and spatial PPI mapping. This necessitates new developments to enhance technical
capabilities for advancing systems structural biology. The ubiquitin-proteasome system (UPS) is the major
degradation pathway in eukaryotes, whose network is remarkably dynamic and made of a large number of
compositionally and structurally dynamic machines that orchestrate protein ubiquitination and degradation.
Dysregulation of the UPS has been linked to many human diseases including cancer and neurodegenerative
disorders. Given the clinical success of proteasome inhibitors, the UPS has become an effective platform for
drug discovery. Although basic functions of the UPS are understood, molecular details underlying its multi-layer
regulation and mechanistic action remain elusive. Therefore, elucidating the interaction and structural dynamics
of the UPS network in its physiological context is essential not only for advancing the understanding of UPS
biology, but also for augmenting their therapeutic potential in human health and medicine. In the next five years,
we plan to address several outstanding technological challenges in PPI studies to better decipher the UPS
pathways, by pursuing the following two research directions: 1) Advancing XL-MS technologies for interactomics
and structural proteomics at the systems-level; 2) Mapping the UPS network to uncover molecular details
underlying protein ubiquitination and degradation. Specifically, we will center our efforts on developing novel XL-
MS technologies to enable in-depth and quantitative analysis of proteome networks with structural details and
enhanced spatial resolution to define cellular functional states. In addition, we will employ the newly established
technologies to delineate action mechanisms of proteasome regulators in protein degradation, investigate Cullin-
RING Ligase mediated protein ubiquitination and di...

## Key facts

- **NIH application ID:** 10405969
- **Project number:** 1R35GM145249-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Lan Huang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $266,283
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405969

## Citation

> US National Institutes of Health, RePORTER application 10405969, Advancing Proteomics Technologies to Decipher the Ubiquitin-Proteasome System (1R35GM145249-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10405969. Licensed CC0.

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