Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes.
Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes.
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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。
DOI：
10.1038/s41467-017-02655-1
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发表时间：
2018-01-23
影响因子：
16.6
通讯作者：
Dickinson BC
中科院分区：
文献类型：
--
作者：
Kathayat RS;Cao Y;Elvira PD;Sandoz PA;Zaballa ME;Springer MZ;Drake LE;Macleod KF;van der Goot FG;Dickinson BC
通过与棕榈酸酯形成硫酯（S-棕榈酰化）对半胱氨酸残基进行可逆修饰是哺乳动物系统中丰富的脂质翻译后修饰（PTM）。在线粒体蛋白上观察到 S-棕榈酰化，这在代谢脂质和线粒体调节之间提供了有趣的潜在联系。然而，尚不清楚线粒体 S-棕榈酰化是否和/或如何受到调节。在此，我们报告了 mitoDPP 的开发，这是一种靶向荧光探针，可测量活细胞线粒体内 S-棕榈酰化“擦除器”、酰基蛋白硫酯酶 (APT) 的活性水平。使用mitoDPPs，我们发现线粒体中有活性的S-去棕榈酰化，部分是由APT1介导的，APT1是一种S-去棕榈酰化酶，之前被认为存在于细胞质和高尔基体上。我们还发现，长链酰基辅酶A细胞质和线粒体调节蛋白的扰动分别导致胞质和线粒体S-脱棕榈酰酶的选择性反应。总而言之，这项工作揭示了线粒体 S-棕榈酰化受到“擦除”酶的主动调节，这些酶对线粒体脂质稳态的变化做出反应。 S-棕榈酰化调节主要在细胞质中进行研究，其在线粒体中的作用尚不清楚。在这里，作者开发了荧光线粒体靶向探针，发现线粒体中发生去棕榈酰化，并且它受到线粒体脂质稳态变化的影响。
The reversible modification of cysteine residues by thioester formation with palmitate (S-palmitoylation) is an abundant lipid post-translational modification (PTM) in mammalian systems. S-palmitoylation has been observed on mitochondrial proteins, providing an intriguing potential connection between metabolic lipids and mitochondrial regulation. However, it is unknown whether and/or how mitochondrial S-palmitoylation is regulated. Here we report the development of mitoDPPs, targeted fluorescent probes that measure the activity levels of “erasers” of S-palmitoylation, acyl-protein thioesterases (APTs), within mitochondria of live cells. Using mitoDPPs, we discover active S-depalmitoylation in mitochondria, in part mediated by APT1, an S-depalmitoylase previously thought to reside in the cytosol and on the Golgi apparatus. We also find that perturbation of long-chain acyl-CoA cytoplasm and mitochondrial regulatory proteins, respectively, results in selective responses from cytosolic and mitochondrial S-depalmitoylases. Altogether, this work reveals that mitochondrial S-palmitoylation is actively regulated by “eraser” enzymes that respond to alterations in mitochondrial lipid homeostasis. S-palmitoylation regulation has been studied mostly in the cytosol and its role in mitochondria is unclear. Here the authors develop fluorescent mitochondria-targeted probes and find that depalmitoylation occurs in mitochondria and it’s influenced by alterations in mitochondrial lipid homeostasis.
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影响因子：
8.4
作者：
Beck MW;Kathayat RS;Cham CM;Chang EB;Dickinson BC
通讯作者：
Dickinson BC
影响因子：
4
作者：
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通讯作者：
Cortassa SC
影响因子：
4.8
作者：
Corvi, MM;Soltys, CLM;Berthiaume, LG
通讯作者：
Berthiaume, LG
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14.8
作者：
Chan P;Han X;Zheng B;DeRan M;Yu J;Jarugumilli GK;Deng H;Pan D;Luo X;Wu X
通讯作者：
Wu X
影响因子：
14.8
作者：
Dekker, Frank J.;Rocks, Oliver;Waldmann, Herbert
通讯作者：
Waldmann, Herbert