Wang Juan, Hu Jijia, Hu Hongtu, Guan Qian, Zhu Zijing, Yang Qian, Ding Guohua
Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Nephrology and Urology Research Institute of Wuhan University, Wuhan, Hubei, China.
Int J Biol Sci. 2025 Jun 9;21(9):3852-3866. doi: 10.7150/ijbs.109220. eCollection 2025.
Cluster of Differentiation 36 (CD36), also known as scavenger receptor B2, plays a critical role in controlling podocyte lipid metabolism, mediating the onset and progression of diabetic kidney disease (DKD). However, the post-translational regulation of CD36 and its exact role in lipid transport within podocytes remain unclear. In this study, we elucidate the mechanism by which acyl-protein thioesterase 1 (APT1) depalmitoylates CD36 in podocytes. We reveal that APT1 interacts with CD36 and reduces its palmitoylation at Cys466 specifically, thereby promoting its trafficking from the plasma membrane to lysosomes for degradation. Diabetes-induced downregulation of APT1 redirects palmitoylated CD36 into the recycling pathway. Consequently, enhanced lipid uptake in podocytes leads to lipotoxicity. Conversely, APT1 overexpression mitigates lipid accumulation by enhancing lysosomal degradation and reducing plasma membrane-associated CD36. Our findings indicate that diabetes-induced APT1 deficiency promotes palmitoylated CD36 enrichment on plasma membranes through decreased APT1 expression, driving lipid overload and podocyte injury.
分化簇36（CD36），也称为清道夫受体B2，在控制足细胞脂质代谢、介导糖尿病肾病（DKD）的发生和发展中起关键作用。然而，CD36的翻译后调控及其在足细胞内脂质转运的确切作用仍不清楚。在本研究中，我们阐明了酰基蛋白硫酯酶1（APT1）使足细胞中CD36去棕榈酰化的机制。我们发现APT1与CD36相互作用，并特异性降低其在半胱氨酸466处的棕榈酰化，从而促进其从质膜向溶酶体的转运以进行降解。糖尿病诱导的APT1下调将棕榈酰化的CD36重定向到再循环途径。因此，足细胞中脂质摄取增加导致脂毒性。相反，APT1过表达通过增强溶酶体降解和减少质膜相关的CD36来减轻脂质积累。我们的研究结果表明，糖尿病诱导的APT1缺乏通过降低APT1表达促进棕榈酰化的CD36在质膜上的富集，导致脂质过载和足细胞损伤。
