A STAT3 palmitoylation cycle promotes T(H)17 differentiation and colitis.
A STAT3 palmitoylation cycle promotes T(H)17 differentiation and colitis.
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DOI：
10.1038/s41586-020-2799-2
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发表时间：
2020-10
期刊：
影响因子：
64.8
通讯作者：
Lin H
中科院分区：
文献类型：
--
作者：
Zhang M;Zhou L;Xu Y;Yang M;Xu Y;Komaniecki GP;Kosciuk T;Chen X;Lu X;Zou X;Linder ME;Lin H
半胱氨酸棕榈酰化（S-棕榈酰化）是一种可逆的翻译后修饰，由棕榈酰转移酶的DHHC家族安装，并被几种酰基蛋白硫酯酶逆转。虽然已知数千种人类蛋白质经历S-棕榈酰化，但对这种修饰如何调节以调节特定的生物学功能知之甚少。在这里，我们报告的关键T辅助17（TH 17）细胞分化刺激，STAT 3，是受可逆的S-棕榈酰化半胱氨酸108。DHHC 7棕榈酰化STAT 3并促进其膜募集和磷酸化。酰基蛋白硫酯酶2（APT 2，也称为LYPLA 2）使磷酸化的STAT 3（p-STAT 3）脱棕榈酰化并使其能够易位到细胞核。这种棕榈酰化-脱棕榈酰化循环增强STAT 3活化并促进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细胞的过度活化与几种炎性疾病有关，包括炎性肠病（IBD）。在小鼠模型中，APT 2的药理学抑制或Zdhhc 7的敲除-其编码DHHC 7 [作者：OK？]-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，而且还揭示了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许多S-棕榈酰化事件的信号传导功能。
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. 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 (TH17) cell differentiation stimulator, STAT3, 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 the phosphorylated STAT3 (p-STAT3) and enables it to translocate to the nucleus. This palmitoylation–depalmitoylation cycle enhances STAT3 activation and promotes TH17 cell differentiation; perturbation of either palmitoylation or depalmitoylation negatively affects TH17 cell differentiation. Overactivation of TH17 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 [Author: OK?]—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.
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靶向荧光探针揭示了主动和动态的线粒体S-脱甲酰化。
影响因子：
16.6
作者：
Kathayat RS;Cao Y;Elvira PD;Sandoz PA;Zaballa ME;Springer MZ;Drake LE;Macleod KF;van der Goot FG;Dickinson BC
通讯作者：
Dickinson BC
影响因子：
4.8
作者：
Fukata, Yuko;Iwanaga, Tsuyoshi;Fukata, Masaki
通讯作者：
Fukata, Masaki
影响因子：
14.8
作者：
Dekker, Frank J.;Rocks, Oliver;Waldmann, Herbert
通讯作者：
Waldmann, Herbert
影响因子：
4.9
作者：
Krag, Aleksander;Munkholm, Pia;Bendtsen, Flemming
通讯作者：
Bendtsen, Flemming
蛋白质棕榈酰化和 zDHHC16 在 DNA 损伤反应中的潜在作用
影响因子：
--
作者：
Cao N;Li JK;Rao YQ;Liu H;Wu J;Li B;Zhao P;Zeng L;Li J
通讯作者：
Li J