# Global analysis of the selectivity of proteostatic pathways

> **NIH NIH R35** · UNIVERSITY OF ROCHESTER · 2021 · $383,178

## Abstract

Summary
Within a cell, a number of pathways contribute to the repair and clearance of proteins and
are required for maintaining protein homeostasis (proteostasis). A common feature of
proteostatic pathways is their ability to act on a range of client proteins that vary based on
cellular and environmental conditions. The molecular mechanisms of the selectivity of many
proteostatic pathways remain incompletely understood. The overall goal of our research
program is to investigate the mechanisms that determine the selectivity of proteostatic
pathways by conducting functional analyses on proteome-wide scales. As a first step
towards this long-term objective, we have focused on investigating the global selectivities of
the macroautophagy pathway and methionine sulfoxide reductases.
Macroautophagy can selectively target specific proteins and organelles for lysosomic
degradation. Using novel proteomic approaches, we have identified subsets of proteins that
rely on macroautophagy for their constitutive turnover. We have also shown that selective
autophagic degradation plays a major role in maintaining protein homeostasis in quiescent
cells and that alterations in autophagic flux is a pathologic feature of prion infected cells.
Our future research will focus on understanding the molecular mechanisms of the
differential selectivity of basal macroautophagy and investigating the prevalence and
regulation of selective macroautophagy in quiescent and prion infected cells.
The methionine sulfoxide reductase (Msr) system is an important repair pathway for
oxidized methionine residues in proteins. To facilitate global analyses of the selectivity of
Msrs, we have developed novel proteomic approaches for accurate quantitation of
methionine oxidation on proteome-wide scales. Using these approaches, we plan to
investigate the extent of methionine oxidation in proteomes of cells and tissues that are
deficient in specific Msrs under normal and oxidative stress conditions.
Together, the proposed experiments will provide insights into the mechanisms of client
selection by macroautophagy and Msr pathways. Our studies will also examine the role of
these two pathways in mitigating protein damage that occurs under specific proteotoxic
stress conditions.

## Key facts

- **NIH application ID:** 10164911
- **Project number:** 2R35GM119502-06
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** SINA GHAEMMAGHAMI
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $383,178
- **Award type:** 2
- **Project period:** 2016-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10164911

## Citation

> US National Institutes of Health, RePORTER application 10164911, Global analysis of the selectivity of proteostatic pathways (2R35GM119502-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10164911. Licensed CC0.

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