# Mechanisms of cytosolic proteostasis in yeast

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $310,585

## Abstract

Nearly 50 major diseases ranging from diabetes to neurodegenerative disorders
including Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s (HD) diseases have been
linked to protein misfolding and aggregation. Cells grow and proliferate under the
constant threat of damage from endogenous reactive oxygen species (ROS), exogenous
oxidants and reactive electrophiles. Cytosolic protein cysteines are almost exclusively
maintained in the reduced state, and cysteine oxidation caused by oxidative stress is
predicted to result in significant misfolding and aggregation. However, relatively little is
known about the consequences of redox imbalance on protein homeostasis
(proteostasis). Furthermore, the roles of cellular reduction-oxidation (redox) buffering
pathways, including the thioredoxin and glutathione systems, in maintaining cytosolic
proteostasis are not well understood. We seek to understand the interplay between
cytoprotective stress response pathways and the machinery employed to maintain
proteostasis. Published and preliminary results detailed in the proposal lead us to
hypothesize that induction of the cytoprotective heat shock response (HSR) by redox
imbalance is mediated in part by a cysteine switch in the principal protein chaperone
Hsp70 (Ssa1 in budding yeast) and that thiol redox buffering plays a significant role in
maintenance of cytosolic proteostasis. The primary objectives of this renewal application
are to determine the impacts of thiol-reactive stress on cytoplasmic protein biogenesis
and protein quality control and to elucidate the regulatory interactions between oxidant
and unfolded protein responses, through three distinct lines of investigation. In Specific
Aim 1 we will define the mechanism by which the key molecular chaperone Ssa1/Hsp70
regulates the HSR through modulation of transcriptional activity by the master heat
shock transcription factor Hsf1. Specific Aim 2 will investigate the consequences of thiol-
reactive stress on Ssa1/Hsp70 activity and cellular functions, including how the
Ssa1/Hsp70 redox switch regulates the HSR, and determine the roles of the highly
conserved redox buffering systems in mediating thiol-reactive stress. In Specific Aim 3,
we will determine the impacts of protein thiol modification on general cytosolic
proteostasis using proteomic and genetic approaches. The work outlined in this proposal
will reveal the mechanistic connections between cellular redox and protein quality control
networks by exploiting the tractable yeast model system. These results in turn will guide
future development of therapeutic interventions targeting ROS- and protein quality
control-based disorders.

## Key facts

- **NIH application ID:** 10126867
- **Project number:** 5R01GM127287-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** KEVIN ANTHONY MORANO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $310,585
- **Award type:** 5
- **Project period:** 2018-04-16 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126867

## Citation

> US National Institutes of Health, RePORTER application 10126867, Mechanisms of cytosolic proteostasis in yeast (5R01GM127287-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10126867. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*