title: 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.
authors.affiliation: 1] Department of Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA [2] Flexus Biosciences, 75 Shoreway Road, Suite D, San Carlos, California 94070, USA (R.N.); American Society for Biochemistry and Molecular Biology, 11200 Rockville Pike, Suite 302, Rockville, Maryland 20852, USA (P.A.V.).
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Noubade
authors.affiliation: Department of Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Kit
authors.initials: K
authors.lastname: Wong
authors.affiliation: Department of Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Naruhisa
authors.initials: N
authors.lastname: Ota
authors.affiliation: Department of Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Sascha
authors.initials: S
authors.lastname: Rutz
authors.affiliation: Department of Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Eidenschenk
authors.affiliation: 1] Department of Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA [2] Flexus Biosciences, 75 Shoreway Road, Suite D, San Carlos, California 94070, USA (R.N.); American Society for Biochemistry and Molecular Biology, 11200 Rockville Pike, Suite 302, Rockville, Maryland 20852, USA (P.A.V.).
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Valdez
authors.affiliation: Department of Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jiabing
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Peng
authors.affiliation: Department of Antibody Engineering, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sebrell
authors.affiliation: Department of Pathology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Caplazi
authors.affiliation: Department of Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: DeVoss
authors.affiliation: Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Soriano
authors.affiliation: Department of Antibody Engineering, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Sai
authors.affiliation: Department of Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Rongze
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.affiliation: Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Hackney
authors.affiliation: Department of Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology*; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053779:Latent TGF-beta Binding Proteins; D008089:Listeria monocytogenes / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010586:Phagocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D053779:Latent TGF-beta Binding Proteins; D008565:Membrane Proteins; C000589026:NRROS protein, mouse; D011506:Proteins; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases
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