# Molecular mechanisms to maintain ER redox balance

> **NIH NIH R01** · CORNELL UNIVERSITY · 2020 · $85,874

## Abstract

Abstract
Reactive oxygen species (ROS) are a significant byproduct of many intracellular and extracellular
events. Cellular systems exist to limit ROS accumulation within cells; a loss of fidelity for these
pathways over time is proposed to contribute towards the excessive intracellular ROS levels
associated with a variety of disease pathologies. Protein folding is particularly susceptible to
disruption upon elevated ROS, and a loss of folding homeostasis has also been linked to the
accumulation of misfolded aggregates in various neurodegenerative disorders. We have uncovered
two novel redox events that make use of ROS to alter the activity of molecular chaperones of the
Hsp70 class during oxidative stress. We propose that these pathways normally serve to maintain
folding homeostasis upon conditions of elevated intracellular ROS. Both events make use of sulfur-
based post-translational events, but each system is unique in the means by which it influences
chaperone activity and cell physiology. Our data suggest that both systems help to maintain normal
cell function during overly oxidizing conditions. This proposal focuses on elucidating the mechanistic
features of these two cellular redox systems. In Aim 1, we continue our characterization of the redox-
signaling pathway we uncovered in the endoplasmic reticulum centered on a thiol-based redox
switch in the Hsp70 BiP. We propose to address how adduct removal from BiP post-stress is
achieved and regulated to maintain folding homeostasis. In Aim 2, we aim to describe the
mechanistic details for a redox switch in the cytoplasmic Hsp70 co-chaperone Fes1. We will
characterize how redox-dependent inactivation of Fes1 via methionine oxidation influences
cytoplasmic Hsp70 function, and how inactivation of Fes1 is advantageous during overly oxidizing
conditions. Successful completion of the proposed studies will provide insight into the basic cell
functions used to manage cellular ROS and avert cellular damage.

## Key facts

- **NIH application ID:** 10135204
- **Project number:** 3R01GM105958-07S1
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Carolyn S Sevier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $85,874
- **Award type:** 3
- **Project period:** 2014-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135204

## Citation

> US National Institutes of Health, RePORTER application 10135204, Molecular mechanisms to maintain ER redox balance (3R01GM105958-07S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10135204. Licensed CC0.

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