Kei Miyano
   Department   Kawasaki Medical School  Kawasaki Medical School, Department of Natural Sciences,
   Position   Assistant Professor
Article types 原著
Language English
Peer review Peer reviewed
Title Regulation of Derlin-1-mediated degradation of NADPH oxidase partner p22phox by thiol modification.
Journal Formal name:Redox Biology
Abbreviation:Redox Biol
ISSN code:22132317
Domestic / ForeginForegin
Publisher Redox Biology
Volume, Issue, Page 56
Author and coauthor Kei Miyano, Shuichiro Okamoto, Mizuho Kajikawa, Takuya Kiyohara, Chikage Kawai, Akira Yamauchi, Futoshi Kuribayashi
Authorship Lead author,Corresponding author
Publication date 2022/09/13
Summary The transmembrane protein p22phox heterodimerizes with NADPH oxidase (Nox) 1-4 and is essential for the reactive oxygen species-producing capacity of oxidases. Missense mutations in the p22phox gene prevent the formation of phagocytic Nox2-based oxidase, which contributes to host defense. This results in chronic granulomatous disease (CGD), a severe primary immunodeficiency syndrome. In this study, we characterized missense mutations in p22phox (L51Q, L52P, E53V, and P55R) in the A22° type (wherein the p22phox protein is undetectable) of CGD. We demonstrated that these substitutions enhanced the degradation of the p22phox protein in the endoplasmic reticulum (ER) and the binding of p22phox to Derlin-1, a key component of ER-associated degradation (ERAD). Therefore, the L51-L52-E53-P55 sequence is responsible for protein stability in the ER. We observed that the oxidation of the thiol group of Cys-50, which is adjacent to the L51-L52-E53-P55 sequence, suppressed p22phox degradation. However, the suppression effect was markedly attenuated by the serine substitution of Cys-50. Blocking the free thiol of Cys-50 by alkylation or C50S substitution promoted the association of p22phox with Derlin-1. Derlin-1 depletion partially suppressed the degradation of p22phox mutant proteins. Furthermore, heterodimerization with p22phox (C50S) induced rapid degradation of not only Nox2 but also nonphagocytic Nox4 protein, which is responsible for redox signaling. Thus, the redox-sensitive Cys-50 appears to determine whether p22phox becomes a target for degradation by the ERAD system through its interaction with Derlin-1.
DOI 10.1016/j.redox.2022.102479
PMID 36122532