Center for Metabolism Research, The Fourth Affiliated Hospital of School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
Nat Metab. 2024 Aug;6(8):1549-1565. doi: 10.1038/s42255-024-01085-w. Epub 2024 Aug 14.
Lipid droplets (LDs) are organelles specialized in the storage of neutral lipids, cholesterol esters and triglycerides, thereby protecting cells from the toxicity of excess lipids while allowing for the mobilization of lipids in times of nutrient deprivation. Defects in LD function are associated with many diseases. S-acylation mediated by zDHHC acyltransferases modifies thousands of proteins, yet the physiological impact of this post-translational modification on individual proteins is poorly understood. Here, we show that zDHHC11 regulates LD catabolism by modifying adipose triacylglyceride lipase (ATGL), the rate-limiting enzyme of lipolysis, both in hepatocyte cultures and in mice. zDHHC11 S-acylates ATGL at cysteine 15. Preventing the S-acylation of ATGL renders it catalytically inactive despite proper localization. Overexpression of zDHHC11 reduces LD size, whereas its elimination enlarges LDs. Mutating ATGL cysteine 15 phenocopies zDHHC11 loss, causing LD accumulation, defective lipolysis and lipophagy. Our results reveal S-acylation as a mode of regulation of ATGL function and LD homoeostasis. Modulating this pathway may offer therapeutic potential for treating diseases linked to defective lipolysis, such as fatty liver disease.
脂滴（LDs）是专门用于储存中性脂质、胆固醇酯和甘油三酯的细胞器，从而保护细胞免受过量脂质的毒性，同时在营养缺乏时允许脂质的动员。LD 功能的缺陷与许多疾病有关。由 zDHHC 酰基转移酶介导的 S-酰化修饰了数千种蛋白质，但这种翻译后修饰对单个蛋白质的生理影响知之甚少。在这里，我们表明 zDHHC11 通过修饰脂肪三酰甘油脂肪酶（ATGL）来调节 LD 分解代谢，ATGL 是脂肪分解的限速酶，在肝细胞培养物和小鼠中均如此。zDHHC11 将 ATGL 的半胱氨酸 15 进行 S-酰化，尽管其定位正确，但使其催化失活。ATGL 的 S-酰化的阻止使其尽管正确定位但仍然无催化活性。zDHHC11 的过表达会减小 LD 大小，而其缺失则会增大 LD 大小。突变 ATGL 的半胱氨酸 15 可模拟 zDHHC11 的缺失，导致 LD 积累、脂肪分解和脂自噬缺陷。我们的结果揭示了 S-酰化作为 ATGL 功能和 LD 动态平衡调节的一种模式。调节这条途径可能为治疗与脂肪分解缺陷相关的疾病提供治疗潜力，例如脂肪肝疾病。
