Journal Article

Role of S-Palmitoylation by ZDHHC13 in Mitochondrial function and Metabolism in Liver

Yen, Jeffrey J. Y., Chen, Yu-Ju, Chen, Yi-Ju, Haddad, Amir N. Saleem, Song, I-Wen, Chen, Li-Ying, Wu, Jer-Yuarn, Shen, Li-Fen, Roan, Hsiao-Yuh, Chen, Yuan-Tsong, Liu, Kai-Ming

2017

Overview

Palmitoyltransferase (PAT) catalyses protein S-palmitoylation which adds 16-carbon palmitate to specific cysteines and contributes to various biological functions. We previously reported that in mice, deficiency of Zdhhc13 , a member of the PAT family, causes severe phenotypes including amyloidosis, alopecia, and osteoporosis. Here, we show that Zdhhc13 deficiency results in abnormal liver function, lipid abnormalities, and hypermetabolism. To elucidate the molecular mechanisms underlying these disease phenotypes, we applied a site-specific quantitative approach integrating an alkylating resin-assisted capture and mass spectrometry-based label-free strategy for studying the liver S-palmitoylome. We identified 2,190 S-palmitoylated peptides corresponding to 883 S-palmitoylated proteins. After normalization using the membrane proteome with TMT10-plex labelling, 400 (31%) of S-palmitoylation sites on 254 proteins were down-regulated in Zdhhc13 -deficient mice, representing potential ZDHHC13 substrates. Among these, lipid metabolism and mitochondrial dysfunction proteins were overrepresented. MCAT and CTNND1 were confirmed to be specific ZDHHC13 substrates. Furthermore, we found impaired mitochondrial function in hepatocytes of Zdhhc13 -deficient mice and Zdhhc13 -knockdown Hep1–6 cells. These results indicate that ZDHHC13 is an important regulator of mitochondrial activity. Collectively, our study allows for a systematic view of S-palmitoylation for identification of ZDHHC13 substrates and demonstrates the role of ZDHHC13 in mitochondrial function and metabolism in liver.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/337/458 / 631/45/475/2290 / 82/58 / 82/80 / Acyltransferases - genetics / Acyltransferases - metabolism / Alopecia / Amyloidosis / Animals / Catenins - genetics / Cell Line / Computational Biology - methods / Enzyme Activation / Hepatocytes / Hepatocytes - metabolism / Humanities and Social Sciences / Labeling / Lipid Metabolism / Liver / Liver - metabolism / Mass spectrometry / Mass spectroscopy / Metabolic Diseases - genetics / Metabolic Diseases - metabolism / Metabolism / Mice / Mice, Knockout / Mitochondria / Mitochondria - genetics / Mitochondria - metabolism / Molecular modelling / multidisciplinary / Osteoporosis / Palmitic acid / Palmitoylation / Palmitoyltransferase / Peptides / Protein S / Protein turnover / Proteins / Proteomes / Rodents / Science / Science (multidisciplinary) / Substrate Specificity