Nrros negatively regulates reactive oxygen species during host defence and autoimmunity
Abstract
Reactive oxygen species (ROS) produced by phagocytes are essential for host defence against bacterial and fungal infections. Individuals with defective ROS production machinery develop chronic granulomatous disease. Conversely, excessive ROS can cause collateral tissue damage during inflammatory processes and therefore needs to be tightly regulated. Here we describe a protein, we termed negative regulator of ROS (NRROS), which limits ROS generation by phagocytes during inflammatory responses. NRROS expression in phagocytes can be repressed by inflammatory signals. NRROS-deficient phagocytes produce increased ROS upon inflammatory challenges, and mice lacking NRROS in their phagocytes show enhanced bactericidal activity against Escherichia coli and Listeria monocytogenes. Conversely, these mice develop severe experimental autoimmune encephalomyelitis owing to oxidative tissue damage in the central nervous system. Mechanistically, NRROS is localized to the endoplasmic reticulum, where it directly interacts with nascent NOX2 (also known as gp91(phox) and encoded by Cybb) monomer, one of the membrane-bound subunits of the NADPH oxidase complex, and facilitates the degradation of NOX2 through the endoplasmic-reticulum-associated degradation pathway. Thus, NRROS provides a hitherto undefined mechanism for regulating ROS production--one that enables phagocytes to produce higher amounts of ROS, if required to control invading pathogens, while minimizing unwanted collateral tissue damage.
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NRROS negatively influences ROS production via Nox2 by competing with p22phox in binding gp91phox.
“The negative regulator of ROS (NRROS), a regulatory factor directly interacting with Nox2, negatively influences ROS production via Nox2 by competing with p22phox in binding gp91phox [245].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [245]
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- Authors
- Noubade, R., Wong, K., Ota, N., Rutz, S., Eidenschenk, C., Valdez, P. A., Ding, J., Peng, I., Sebrell, A., Caplazi, P., DeVoss, J., Soriano, R. H., Sai, T., Lu, R., Modrusan, Z., Hackney, J., & Ouyang, W.
- Affiliations
- Genentech (US)
- Corresponding author
- Ouyang, Wenjun
- ORCID
- Venue
- Nature
- Published
- 2014-04-13
- Volume
- 509
- Issue
- 7499
- Pages
- 235-239
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2090106964
- Cited by
- 246
- References
- 39
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 20 · 2023: 22 · 2022: 18 · 2021: 18 · 2020: 24 · 2019: 22 · 2018: 20 · 2017: 21 · 2016: 25 · 2015: 15 · 2014: 7
- FWCI
- 10.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- reactive oxygen species, NADPH oxidase, NOX2, gp91phox, endoplasmic reticulum, ER-associated degradation, phagocytes, host defense, autoimmunity, experimental autoimmune encephalomyelitis, Escherichia coli, Listeria monocytogenes, collateral tissue damage, inflammation, leucine-rich repeat proteins
- MeSH terms
- Animals, Bone Marrow Cells, Central Nervous System, Encephalomyelitis, Autoimmune, Experimental, Endoplasmic Reticulum, Escherichia coli, Female, Inflammation, Listeria monocytogenes, Macrophages, Male, Membrane Proteins, Oxidation-Reduction, Phagocytes, Proteins, Autoimmunity, Reactive Oxygen Species, Oxidative Stress, NADPH Oxidases, Mice, Latent TGF-beta Binding Proteins
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