ヤマウチ　アキラ   Akira Yamauchi   山内　明    所属   川崎医科大学  医学部 基礎医学　生化学    職種   教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Regulation of Derlin-1-mediated degradation of NADPH oxidase partner p22phox by thiol modification.
掲載誌名	正式名：Redox Biology 略　 称：Redox Biol ISSNコード：22132317
掲載区分	国外
出版社	Redox Biology
巻・号・頁	56
著者・共著者	Kei Miyano, Shuichiro Okamoto, Mizuho Kajikawa, Takuya Kiyohara, Chikage Kawai, Akira Yamauchi, Futoshi Kuribayashi
発行年月	2022/09/13
概要	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