Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes

作者：Kathayat Rahul S; Cao Yang; Elvira Pablo D; Sandoz Patrick A; Zaballa Maria Eugenia; Springer Maya Z; Drake Lauren E; Macleod Kay F; van der Goot F Gisou^*; Dickinson Bryan C^*

来源：Nature Communications, 2018, 9(1): 334.

DOI：10.1038/s41467-017-02655-1

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.

• 出版日期2018-1-23