Kondo Moe, Nishiyama Kazuhiro, Nishimura Akiyuki, Kato Yuri, Nishida Motohiro
Department of Physiology, Graduate School of Pharmaceutical Sciences Kyushu University.
Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences.
Nihon Yakurigaku Zasshi. 2022;157(5):356-360. doi: 10.1254/fpj.22045.
G protein-coupled receptors (GPCRs) play pivotal roles in converting physicochemical stimuli due to environmental changes to intracellular responses. After ligand stimulation, many GPCRs are desensitized and then recycled or degraded through phosphorylation and β-arrestin-dependent internalization, an important process to maintain protein quality control of GPCRs. However, it is unknown how GPCRs with low β-arrestin sensitivity are controlled. Here we unmasked a β-arrestin-independent GPCR internalization, named Redox-dependent Alternative Internalization (REDAI), focusing on β-arrestin-resistant purinergic P2Y receptor (P2YR). P2YR is highly expressed in macrophage and pathologically contributes to the development of colitis in mice. Natural electrophiles including in functional foods induce REDAI-mediated P2YR degradation leading to anti-inflammation in macrophages. Prevention of Cys220 modification on P2YR resulted in aggravation of the colitis. These results strongly suggest that targeting REDAI on GPCRs will be a breakthrough strategy for the prevention and treatment of inflammatory diseases.
G蛋白偶联受体（GPCRs）在将环境变化引起的物理化学刺激转化为细胞内反应方面发挥着关键作用。配体刺激后，许多GPCRs会脱敏，然后通过磷酸化和β-抑制蛋白依赖性内化进行再循环或降解，这是维持GPCRs蛋白质质量控制的重要过程。然而，低β-抑制蛋白敏感性的GPCRs如何被调控尚不清楚。在这里，我们揭示了一种不依赖β-抑制蛋白的GPCR内化，称为氧化还原依赖性替代内化（REDAI），重点研究对β-抑制蛋白有抗性的嘌呤能P2Y受体（P2YR）。P2YR在巨噬细胞中高度表达，在病理上促进小鼠结肠炎的发展。包括功能性食品中的天然亲电试剂可诱导REDAI介导的P2YR降解，从而导致巨噬细胞抗炎。P2YR上Cys220修饰的预防导致结肠炎加重。这些结果强烈表明，针对GPCRs上的REDAI将是预防和治疗炎症性疾病的突破性策略。
