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（LD）是专门储存中性脂质、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，同时允许在营养缺乏时动员脂质。 LD 功能缺陷与许多疾病有关。 zDHHC 酰基转移酶介导的 S-酰化可修饰数千种蛋白质，但这种翻译后修饰对单个蛋白质的生理影响却知之甚少。在这里，我们表明，在肝细胞培养物和小鼠中，zDHHC11 通过修饰脂肪三酰甘油脂肪酶 (ATGL)（脂肪分解的限速酶）来调节 LD 分解代谢。 zDHHC11 在半胱氨酸 15 处 S-酰化 ATGL。尽管定位正确，但阻止 ATGL 的 S-酰化使其催化失活。 zDHHC11 的过度表达会减小 LD 大小，而其消除则会增大 LD。突变的 ATGL 半胱氨酸 15 表型 zDHHC11 丢失，导致 LD 积累、脂肪分解和脂肪吞噬缺陷。我们的结果揭示了 S-酰化是 ATGL 功能和 LD 稳态的调节模式。调节该途径可能为治疗与脂肪分解缺陷相关的疾病（例如脂肪肝病）提供治疗潜力。