Oxidized high-density lipoprotein promotes CD36 palmitoylation and increases lipid uptake in macrophages

Zhang, Yun; Dong, Doudou; Xu, Xiaoting; He, Hui; Zhu, Yuan; Tong, Lei; Ou, Hailong

doi:10.1016/j.jbc.2022.102000

Cited by 26 publications

(15 citation statements)

References 45 publications

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“…Palmitoylation can be catalyzed by palmitoyltransferases, also called DHHC, because of their conserved Asp-His-His-Cys sequence and can be removed by acyl protein thioesterases [ [80] , [81] , [82] ]. Recent studies have found that SelK as a cofactor of the palmitoyltransferase DHHC6 in mediating CD36 palmitoylation, thus aggravates foam cell formation and atherogenesis [ 83 , 84 ]. We verified this notion using different approaches and obtained the similar result.…”

Section: Discussionmentioning

confidence: 99%

Selenoprotein K contributes to CD36 subcellular trafficking in hepatocytes by accelerating nascent COPII vesicle formation and aggravates hepatic steatosis

You¹,

Wu²,

Gao³

et al. 2022

Redox Biology

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Section: Discussionmentioning

confidence: 99%

Selenoprotein K contributes to CD36 subcellular trafficking in hepatocytes by accelerating nascent COPII vesicle formation and aggravates hepatic steatosis

You¹,

Wu²,

Gao³

et al. 2022

Redox Biology

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“…36 ZDHHC6 also palmitoylates CD36, which is reported to promote lipid uptake in macrophages and the formation of foam cells. 37 The promotion of lipid uptake by ZDHHC6 via CD36 is particularly interesting and may also be connected to liver diseases, such as NASH. The exact mechanism via which S-palmitoylation negatively affects AEG-1 function awaits further studies in the future.…”

Section: ■ Discussionmentioning

confidence: 99%

“…For example, ZDHHC6 is reported to palmitoylate MYD88 and promote Toll-like receptor signaling . ZDHHC6 also palmitoylates CD36, which is reported to promote lipid uptake in macrophages and the formation of foam cells . The promotion of lipid uptake by ZDHHC6 via CD36 is particularly interesting and may also be connected to liver diseases, such as NASH.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte Elevated Gene-1 Cys75 S-Palmitoylation by ZDHHC6 Regulates Its Biological Activity

et al. 2022

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Nonalcoholic fatty liver disease is a major risk factor for hepatocellular carcinoma (HCC). Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) augments lipid accumulation (steatosis), inflammation, and tumorigenesis, thereby promoting the whole spectrum of this disease process. Targeting AEG-1 is a potential interventional strategy for nonalcoholic steatohepatitis (NASH) and HCC. Thus, proper understanding of the regulation of this molecule is essential. We found that AEG-1 is palmitoylated at residue cysteine 75 (Cys75). Mutation of Cys75 to serine (Ser) completely abolished AEG-1 palmitoylation. We identified ZDHHC6 as a palmitoyltransferase catalyzing the process in HEK293T cells. To obtain insight into how palmitoylation regulates AEG-1 function, we generated knock-in mice by CRISPR/Cas9 in which Cys75 of AEG-1 was mutated to Ser (AEG-1-C75S). No developmental or anatomical abnormality was observed between AEG-1-wild type (AEG-1-WT) and AEG-1-C75S littermates. However, global gene expression analysis by RNAsequencing unraveled that signaling pathways and upstream regulators, which contribute to cell proliferation, motility, inflammation, angiogenesis, and lipid accumulation, were activated in AEG-1-C75S hepatocytes compared to AEG-1-WT. These findings suggest that AEG-1-C75S functions as dominant positive and that palmitoylation restricts oncogenic and NASH-promoting functions of AEG-1. We thus identify a previously unknown regulatory mechanism of AEG-1, which might help design new therapeutic strategies for NASH and HCC.

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“…The precise localization of calcineurin CNAβ1 and CD36 is also regulated by palmitoylation 674 . Palmitoylation enhances the hydrophobicity of CD36, 675 increasing its ability to bind to the membrane and absorb fatty acids 676 . In contrast, inhibiting CD36 palmitoylation reduces its hydrophobicity and localization to the cytoplasmic membrane 677 .…”

Section: Long‐chain Fatty Acid Modificationsmentioning

confidence: 99%

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

Zhong

Xiao

Xie

et al. 2023

MedComm

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Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on the backbones or amino acid side chains of proteins and expand the diversity of proteins, which provides the basis for the emergence of organismal complexity. To date, more than 650 types of protein modifications, such as the most well‐known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short‐chain and long‐chain acylation modifications, redox modifications, and irreversible modifications, have been described, and the inventory is still increasing. By changing the protein conformation, localization, activity, stability, charges, and interactions with other biomolecules, PTMs ultimately alter the phenotypes and biological processes of cells. The homeostasis of protein modifications is important to human health. Abnormal PTMs may cause changes in protein properties and loss of protein functions, which are closely related to the occurrence and development of various diseases. In this review, we systematically introduce the characteristics, regulatory mechanisms, and functions of various PTMs in health and diseases. In addition, the therapeutic prospects in various diseases by targeting PTMs and associated regulatory enzymes are also summarized. This work will deepen the understanding of protein modifications in health and diseases and promote the discovery of diagnostic and prognostic markers and drug targets for diseases.

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Oxidized high-density lipoprotein promotes CD36 palmitoylation and increases lipid uptake in macrophages

Cited by 26 publications

References 45 publications

Selenoprotein K contributes to CD36 subcellular trafficking in hepatocytes by accelerating nascent COPII vesicle formation and aggravates hepatic steatosis

Selenoprotein K contributes to CD36 subcellular trafficking in hepatocytes by accelerating nascent COPII vesicle formation and aggravates hepatic steatosis

Astrocyte Elevated Gene-1 Cys75 S-Palmitoylation by ZDHHC6 Regulates Its Biological Activity

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

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