# Molecular mechanisms to maintain ER redox balance

> **NIH NIH R01** · CORNELL UNIVERSITY · 2022 · $323,439

## 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:** 10316207
- **Project number:** 5R01GM105958-09
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Carolyn S Sevier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $323,439
- **Award type:** 5
- **Project period:** 2014-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10316207

## Citation

> US National Institutes of Health, RePORTER application 10316207, Molecular mechanisms to maintain ER redox balance (5R01GM105958-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10316207. Licensed CC0.

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