Regulation of chemokine signaling by post-translational modification of beta-arrestin and relationship with atherosclerosis

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08515
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Osaka University
• Principal Investigator: Hayashi Hiroki 大阪大学, 医学系研究科, 寄附講座講師 (20813364)
• Co-Investigator(Kenkyū-buntansha): 中神 啓徳 大阪大学, 医学系研究科, 寄附講座教授 (20325369)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 動脈硬化 / 翻訳後修飾 / ケモカイン

Outline of Final Research Achievements

beta-arrestin, known as an adaptor protein of G protein coupled receptors (GPCR), reported to regulates GPCR signaling via a post-translational modification, S-nitrosylation. We evaluated whether chemokine signaling, CX3CR1 receptor signaling, is modulated by S-nitrosylation of beta-arrestin, and whether S-nitosylation-mediated signaling affects the pathology of atherosclerosis in this study.
We found that S-nitorsylation of beta-arrestin biased chemokine signaling toward G-protein mediated signaling, versus beta-arrestin-mediated signaling, and that chemokine-induced macrophage migration was enhanced by S-nitrosylation of beta-arrstin. These results suggested that biased signaling of CX3CR1 by S-nitrosylation might regulate chemokine signaling, and affect pathogenesis of atherosclerosis by enhancement of microphage migration.

Free Research Field

循環器基礎

Academic Significance and Societal Importance of the Research Achievements

これまで心不全において薬剤の重要なターゲットであるGPCR受容体シグナルはアレスチンの一酸化窒素翻訳後修飾によってシグナルが調節され病態に大きく関与することを見出している。今回、動脈硬化病態形成時に重要な役割が知られているCX3CR1ケモカイン受容体に着目し、同様にアレスチンの翻訳後修飾によってシグナル伝達が調節され、遊走活性など動脈硬化プロセスに関与しうるかどうかを検討することで新規治療法や診断法の開発につながることが期待される。