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Cited by 231Neutrophil, Myeloperoxidase and Oxidative MechanismsRedox biology and oxidative stressNitric Oxide and Endothelin Effects

Point Mutations in the Proline-rich Region of p22 Are Dominant Inhibitors of Nox1- and Nox2-dependent Reactive Oxygen Generation

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Kawahara, Tsukasa, Ritsick, Darren, Cheng, Guangjie, Lambeth, J. David·2005·Journal of Biological Chemistry
DOI 10.1074/jbc.m501882200
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Abstract

The integral membrane protein p22phox is an indispensable component of the superoxide-generating phagocyte NADPH oxidase, whose catalytic core is the membrane-associated gp91phox (also known as Nox2). p22phox associates with gp91phox and, through its proline-rich C terminus, provides a binding site for the tandem Src homology 3 domains of the activating subunit p47phox. Whereas p22phox is expressed ubiquitously, its participation in regulating the activity of other Nox enzymes is less clear. This study investigates the requirement of p22phox for Nox enzyme activity and explores the role of its proline-rich region (PRR) for regulating activity. Coexpression of specific Nox catalytic subunits (Nox1, Nox2, Nox3, Nox4, or Nox5) along with their corresponding regulatory subunits (NOXO1/NOXA1 for Nox1; p47phox/p67phox/Rac for Nox2; NOXO1 for Nox3; no subunits for Nox4 or Nox5) resulted in marked production of reactive oxygen. Small interfering RNAs decreased endogenous p22phox expression and inhibited reactive oxygen generation from Nox1, Nox2, Nox3, and Nox4 but not Nox5. Truncated forms of p22phox that disrupted the PRR-inhibited reactive oxygen generation from Nox1, Nox2, and Nox3 but not from Nox4 and Nox5. Similarly, p22phox (P156Q), a mutation that disrupts Src homology 3 binding by the PRR, potently inhibited reactive oxygen production from Nox1 and Nox2 but not from Nox4 and Nox5. Expression of p22phox (P156Q) inhibited NOXO1-stimulated Nox3 activity, but co-expression of NOXA1 overcame the inhibitory effect. The P157Q and P160Q mutations of p22phox showed selective inhibition of Nox2/p47phox/p67phox, and selectivity was specific for the organizing subunit (p47phox or NOXO1) rather than the Nox catalytic subunit. These studies stress the importance of p22phox for the function of Nox1, Nox2, Nox3, and Nox4, and emphasize the key role of the PRR for regulating Nox proteins whose activity is dependent upon p47phox or NOXO1.

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  • Like Nox2, Nox1 is a transmembrane protein that forms a heterodimer with p22phox and generates O2−.

    “Like Nox2, Nox1 is a transmembrane protein which forms a heterodimer with p22 phox and generates O 2 ⅐Ϫ (Ambasta et al., 2004;Kawahara et al., 2005).”

    From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Kawahara et al., 2005

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Authors
Kawahara, T., Ritsick, D., Cheng, G., & Lambeth, J. D.
Affiliations
Emory University (US)
Corresponding author
Lambeth, J. David
ORCID
Cheng, Guangjie
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2005-09
Volume
280
Issue
36
Pages
31859-31869
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m501882200
OpenAlex
W2008149338
Cited by
231
References
3
Citations by year
2026: 1 · 2025: 3 · 2024: 4 · 2023: 17 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 11 · 2016: 7 · 2015: 7 · 2014: 19 · 2013: 14 · 2012: 16
FWCI
7.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (CA-84138, R01CA084138, CA 105116)
  • National Institute of General Medical Sciences (GM067717, R01GM067717)
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
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
p22phox, NOX1, NOX2, NOX3, NOX4, NADPH oxidase 5, NADPH oxidase, superoxide, proline-rich region, point mutations, p47phox, p67phox, NOXO1, NOXA1, SH3 domain binding
MeSH terms
NADPH Oxidase 1, NADPH Oxidase 2, NADPH Oxidase 4, Cell Line, Humans, Membrane Glycoproteins, Membrane Proteins, Molecular Sequence Data, Phosphoproteins, Proline, RNA, Messenger, Point Mutation, Reactive Oxygen Species, NADPH Oxidases, Amino Acid Substitution, Membrane Transport Proteins, RNA, Small Interfering

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