# Redox Regulation of Heme Oxygenase-2 and the Nuclear Receptor Rev-Erb-beta by their Heme Responsive Motifs

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $332,777

## Abstract

We propose to determine how the heme responsive motif (HRM) promotes regulation of the structure,
function and proteasomal degradation of two proteins with key metabolic roles: Rev-erbβ and heme
oxygenase-2 (HO-2). Our working hypothesis is that the HRMs confer the ability to be regulated by heme,
redox and gaseous signaling molecules (CO, NO, H2S) and by proteasomal degradation.
 Rev-erbβ is a heme-responsive nuclear hormone receptor, which links the circadian clock to metabolism
and inflammation by acting as a transcriptional repressor of diverse genes involved in lipid, glucose and bile
acid metabolism as well as regulating the circadian cycle, cellular differentiation and the proinflammatory
response. Our guiding hypothesis is that the HRMs in Rev-erbβ constitute thiol-disulfide redox switches that
link oxidative stress to the circadian cycle and to metabolic regulation. Our two aims related to Rev-erbβ are
to: (1) determine how the C384-C374 thiol-disulfide redox switch affects Rev-erbβ repressor activity,
proteosomal degradation and interaction with partner proteins and (2) quantify how the state of the HRM-
bound heme affects the properties of Rev-erbβ.
 HO1 and HO2 catalyze the rate-limiting step in O2-dependent degradation of heme to biliverdin, CO and
Fe with electrons delivered from NADPH via cytochrome P450 reductase (CPR). With respect to characterizing
the properties of the HRMs in human HO2, which sits at the nexus of major cellular redox and metal regulatory
systems, we plan to: (3) perform kinetic, spectroscopic and hydrogen-deuterium exchange mass spectrometric
(HDX-MS) studies to investigate heme transfer from the HRMs in the tail to the catalytic core of HO2 and
interactions between the tail and core; (4) determine the role of the N-terminal extension of HO2; and (5)
determine the effect of the HRM on stability of HO2.
 Our studies will reveal how HRMs regulate Rev-erbβ, which, helping explain why abnormal circadian
rhythms are associated with cancer, disturbances in the cell cycle and metabolic disorders. Our research will
also help understand how HO2 is involved in cellular protection against renal, cardiovascular and central
nervous system pathologies induced by oxidative stress by controlling the cellular levels of heme, biliverdin,
iron and carbon monoxide.

## Key facts

- **NIH application ID:** 9852603
- **Project number:** 5R01GM123513-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Stephen Wiley Ragsdale
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $332,777
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852603

## Citation

> US National Institutes of Health, RePORTER application 9852603, Redox Regulation of Heme Oxygenase-2 and the Nuclear Receptor Rev-Erb-beta by their Heme Responsive Motifs (5R01GM123513-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9852603. Licensed CC0.

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