Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Shen LF

PROVIDER: S-EPMC5438363 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Shen Li-Fen LF Chen Yi-Ju YJ Liu Kai-Ming KM Haddad Amir N Saleem ANS Song I-Wen IW Roan Hsiao-Yuh HY Chen Li-Ying LY Yen Jeffrey J Y JJY Chen Yu-Ju YJ Wu Jer-Yuarn JY Chen Yuan-Tsong YT

Scientific reports 20170519 1

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 d ...[more]

PMID: 28526873

Similar Datasets

Project description:BackgroundProtein palmitoylation, which is catalyzed by palmitoyl-transferase and de-palmitoyl-transferase, plays a crucial role in various biological processes. However, the landscape and dynamics of protein palmitoylation in human cancers are not well understood.MethodsWe utilized 23 palmitoyl-acyltransferases and seven de-palmitoyl-acyltransferases as palmitoylation-related genes for protein palmitoylation analysis. Multiple publicly available datasets were employed to conduct pan-cancer analysis, examining the transcriptome, genomic alterations, clinical outcomes, and correlation with c-Myc (Myc) for palmitoylation-related genes. Real-time quantitative PCR and immunoblotting were performed to assess the expression of palmitoylation-related genes and global protein palmitoylation levels in cancer cells treated with Myc depletion or small molecule inhibitors. Protein docking and drug sensitivity analyses were employed to predict small molecules that target palmitoylation-related genes.ResultsWe identified associations between palmitoylation and cancer subtype, stage, and patient survival. We discovered that abnormal DNA methylation and oncogenic Myc-driven transcriptional regulation synergistically contribute to the dysregulation of palmitoylation-related genes. This dysregulation of palmitoylation was closely correlated with immune infiltration in the tumor microenvironment and the response to immunotherapy. Importantly, dysregulated palmitoylation was found to modulate canonical cancer-related pathways, thus influencing tumorigenesis. To support our findings, we performed a proof-of-concept experiment showing that depletion of Myc led to reduced expression of most palmitoylation-related genes, resulting in decreased global protein palmitoylation levels. Through mass spectrometry and enrichment analyses, we also identified palmitoyl-acyltransferases ZDHHC7 and ZDHHC23 as significant contributors to mTOR signaling, DNA repair, and immune pathways, highlighting their potential roles in tumorigenesis. Additionally, our study explored the potential of three small molecular (BI-2531, etoposide, and piperlongumine) to modulate palmitoylation by targeting the expression or activity of palmitoylation-related genes or enzymes.ConclusionsOverall, our findings underscore the critical role of dysregulated palmitoylation in tumorigenesis and the response to immunotherapy, mediated through classical cancer-related pathways and immune cell infiltration. Additionally, we propose that the aforementioned three small molecule hold promise as potential therapeutics for modulating palmitoylation, thereby offering novel avenues for cancer therapy.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets