Cysteine palmitoylation (S-palmitoylation) is a reversible post-translational modification that is installed by the DHHC family of palmitoyltransferases and is reversed by several acyl protein thioesterases 1 , 2 . Although thousands of human proteins are known to undergo S-palmitoylation, how this modification is regulated to modulate specific biological functions is poorly understood. Here we report that the key T helper 17 (T H 17) cell differentiation stimulator, STAT3 3 , 4 , is subject to reversible S-palmitoylation on cysteine 108. DHHC7 palmitoylates STAT3 and promotes its membrane recruitment and phosphorylation. Acyl protein thioesterase 2 (APT2, also known as LYPLA2) depalmitoylates phosphorylated STAT3 (p-STAT3) and enables it to translocate to the nucleus. This palmitoylation–depalmitoylation cycle enhances STAT3 activation and promotes T H 17 cell differentiation; perturbation of either palmitoylation or depalmitoylation negatively affects T H 17 cell differentiation. Overactivation of T H 17 cells is associated with several inflammatory diseases, including inflammatory bowel disease (IBD). In a mouse model, pharmacological inhibition of APT2 or knockout of Zdhhc7 —which encodes DHHC7—relieves the symptoms of IBD. Our study reveals not only a potential therapeutic strategy for the treatment of IBD but also a model through which S-palmitoylation regulates cell signalling, which might be broadly applicable for understanding the signalling functions of numerous S-palmitoylation events. The dynamic and reversible S-palmitoylation of the transcription factor STAT3 enhances its activation and promotes the differentiation of T H 17 cells.

中文翻译：

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STAT3 棕榈酰化循环促进 TH17 分化和结肠炎

半胱氨酸棕榈酰化 (S-palmitoylation) 是一种可逆的翻译后修饰，由 DHHC 棕榈酰转移酶家族安装，并被几种酰基蛋白硫酯酶 1、2 逆转。尽管已知数以千计的人类蛋白质会发生 S-棕榈酰化，但人们对如何调节这种修饰以调节特定的生物学功能知之甚少。在这里，我们报告了关键的 T 辅助 17 (TH 17) 细胞分化刺激物 STAT3 3, 4，在半胱氨酸 108 上发生可逆的 S-棕榈酰化。DHHC7 棕榈酰化 STAT3 并促进其膜募集和磷酸化。酰基蛋白硫酯酶 2 (APT2，也称为 LYPLA2) 使磷酸化的 STAT3 (p-STAT3) 脱棕榈酰化并使其转移到细胞核。这种棕榈酰化-脱棕榈酰化循环增强了 STAT3 激活并促进了 TH 17 细胞分化；棕榈酰化或脱棕榈酰化的扰动对 TH 17 细胞分化产生负面影响。TH 17 细胞的过度激活与多种炎症性疾病有关，包括炎症性肠病 (IBD)。在小鼠模型中，药理学抑制 APT2 或敲除编码 DHHC7 的 Zdhhc7 可缓解 IBD 的症状。我们的研究不仅揭示了治疗 IBD 的潜在治疗策略，而且揭示了 S-棕榈酰化调节细胞信号传导的模型，这可能广泛适用于理解众多 S-棕榈酰化事件的信号传导功能。