# Signaling mechanisms that detect stress and maintain homeostasis

> **NIH NIH R35** · JOSLIN DIABETES CENTER · 2020 · $498,332

## Abstract

Project Summary
 This MIRA proposal focuses on two overlapping areas: stress response regulation and the functions of
redox-based signaling in vivo. It is a fundamentally important problem how organisms detect and respond to
different forms of stress. Much has been learned in this area but we still have a very incomplete understanding
of how some stresses are detected, including reactive small molecules such as ROS. For many years my
group has studied stress responses and aging in C. elegans, focusing on the Nrf2 transcription factor ortholog
SKN-1. Nrf2 mediates a conserved detoxification response to reactive small molecules but has many
additional functions, and is of great importance in health and disease. Working in C. elegans we have defined
a number of aspects of SKN-1/Nrf2 regulation and functions, including its major role in longevity assurance.
 We have recently uncovered an exciting mechanism of SKN-1/Nrf regulation that forms the basis for
this new research direction. We find that SKN-1 and human Nrf2 are activated at the ER by a localized ROS
signal that can derive from the ER, NOX enzyme activation induced by stress, or mitochondria. This signal
induces sulfenylation of a single Cys within the kinase activation loop of the ER unfolded protein sensor IRE-1,
resulting in acute inhibition of the IRE-1 unfolded protein response and activation of p38 signaling at IRE-1
through a second sulfenylation event. p38 signaling in turn activates SKN-1/Nrf2. Remarkably, other kinases
of major interest (AKT, p70S6K, ROCK1) seem to be regulated through sulfenylation of the same Cys. The
data reveal an unexpected IRE-1 function that is regulated by a redox switch, a major stress sensor for SKN-
1/Nrf2, and a possible rationale for how redox stress can affect so many cellular processes. They also suggest
that the scope and functional versatility of Cys-based signaling are much wider than is generally appreciated.
 In our proposed research we will continue to identify mechanisms of SKN-1/Nrf2 regulation and their
functions in vivo, but will also cast our net wider in utilizing the advantages of C. elegans to explore
mechanisms and functions of Cys redox signaling in the context of stress, growth, and other conditions. We
will refine models for IRE-1 regulation of SKN-1/Nrf2 and its functions in vivo. We will also similarly study SKN-
1/Nrf2 regulation by the chaperone TRIC, another mechanism we have identified that may involve redox
signaling, and build upon screening results to develop new models for SKN-1/Nrf2 regulation. Using mass
spectrometry (MS), we will collaboratively identify C. elegans proteins that are Cys-sulfenylated under stress
and growth conditions. We will investigate regulatory and in vivo implications of this modification for the
kinases indicated above, and candidates chosen from our MS data. C. elegans will be ideal for this work
because of the relative rapidity of Cas9/CRISPR genome editing, and phenotypic analyses. Our research ...

## Key facts

- **NIH application ID:** 9942271
- **Project number:** 5R35GM122610-04
- **Recipient organization:** JOSLIN DIABETES CENTER
- **Principal Investigator:** T Keith Blackwell
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $498,332
- **Award type:** 5
- **Project period:** 2017-07-20 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942271

## Citation

> US National Institutes of Health, RePORTER application 9942271, Signaling mechanisms that detect stress and maintain homeostasis (5R35GM122610-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9942271. Licensed CC0.

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