Protein S‐Palmitoylation: advances and challenges in studying a therapeutically important lipid modification

Main, Alice; Fuller, William

doi:10.1111/febs.15781

Cited by 67 publications

(98 citation statements)

References 162 publications

(222 reference statements)

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“…In contrast to S-palmitoylation, N-palmitoylation is an irreversible and poorly understood process. However, few studies support the role of N-palmitoylation in protein function and localization [12,13]. In this review, we summarize and discuss the current knowledge on the impact of S-palmitoylation, one of the most common forms of protein lipidation, on protein signaling, translocation, and interactions in innate immune cells, macrophages in particular.…”

Section: Protein Acetylationmentioning

confidence: 98%

“…While zDHHC7 and zDHHC8 are specific to the Golgi apparatus, zDHHC6 and zDHHC13 are specific to the endoplasmic reticulum. On the other hand, zDHHC5, zDHHC20, and zDHHC21 are primarily localized at the plasma membrane [13,22]. In contrast, APTs are mainly situated in the cytosol but are, in small proportions, also present in the plasma and nuclear membrane, as well as the endoplasmic reticulum [31,32].…”

Section: S-palmitoylationmentioning

confidence: 99%

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Protein Lipidation by Palmitate Controls Macrophage Function

Guns

Vanherle

Hendriks

et al. 2022

Cells

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Macrophages are present in all tissues within our body, where they promote tissue homeostasis by responding to microenvironmental triggers, not only through clearance of pathogens and apoptotic cells but also via trophic, regulatory, and repair functions. To accomplish these divergent functions, tremendous dynamic fine-tuning of their physiology is needed. Emerging evidence indicates that S-palmitoylation, a reversible post-translational modification that involves the linkage of the saturated fatty acid palmitate to protein cysteine residues, directs many aspects of macrophage physiology in health and disease. By controlling protein activity, stability, trafficking, and protein–protein interactions, studies identified a key role of S-palmitoylation in endocytosis, inflammatory signaling, chemotaxis, and lysosomal function. Here, we provide an in-depth overview of the impact of S-palmitoylation on these cellular processes in macrophages in health and disease. Findings discussed in this review highlight the therapeutic potential of modulators of S-palmitoylation in immunopathologies, ranging from infectious and chronic inflammatory disorders to metabolic conditions.

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Section: Protein Acetylationmentioning

confidence: 98%

Section: S-palmitoylationmentioning

confidence: 99%

Protein Lipidation by Palmitate Controls Macrophage Function

Guns

Vanherle

Hendriks

et al. 2022

Cells

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“…This posttranslational modification involves the addition of the C16 acyl chain to the cysteine residue in the protein by means of a thioester bond. This process is reversible, and is carried out by a complex of enzymes [ 265 , 266 , 267 ]. The main function of palmitoylation for many proteins is to increase the affinity for membranes, which contributes to its stable binding to lipid microdomains [ 265 , 268 , 269 ].…”

Section: The Intersection Of Endothelial Biomechanical Properties and Protein Functionmentioning

confidence: 99%

“…Palmitoylation of eNOS stabilizes its association with the membrane and localization in caveolae, and is necessary for its normal functional activity [ 264 , 270 , 271 , 272 , 273 , 274 ]. eNOS with impaired palmitoylation is characterized by lower nitric oxide production [ 176 , 266 ].…”

Section: The Intersection Of Endothelial Biomechanical Properties and Protein Functionmentioning

confidence: 99%

Diversity of Lipid Function in Atherogenesis: A Focus on Endothelial Mechanobiology

Kotlyarov

2021

IJMS

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Atherosclerosis is one of the most important problems in modern medicine. Its high prevalence and social significance determine the need for a better understanding of the mechanisms of the disease’s development and progression. Lipid metabolism and its disorders are one of the key links in the pathogenesis of atherosclerosis. Lipids are involved in many processes, including those related to the mechanoreception of endothelial cells. The multifaceted role of lipids in endothelial mechanobiology and mechanisms of atherogenesis are discussed in this review. Endothelium is involved in ensuring adequate vascular hemodynamics, and changes in blood flow characteristics are detected by endothelial cells and affect their structure and function.

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“…Despite its physiological importance, the biochemical mechanism governing WNT acylation by PORCN is poorly understood. In all, there is an unusual O-acyl modification with palmitoleic acid (9-cis-hexadecenoic or 9-16:1) at a conserved serine residue (Main and Fuller, 2021). Following synthesis, WNT proteins are processed in the ER, where the conserved signal sequence is cleaved before glycosylation and fatty acylation.…”

Section: Palmitoyleation Of Wntmentioning

confidence: 99%

Investigating the Role of Porcupine and WNTless: Components of WNT Signalling Pathway in Response to Endoplasmic Reticulum, Oxidative, Hypoxia and Environmental Toxins Stesses

Mohamed¹

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Porcupine (PORCN) and WNTless (WLS) are factors that control the production of WNT; a protein involved in the early stages of colon cancer development. The WNT proteins play a role in stem cell development and cell differentiation. However, the response of PORCN and WLS to stressors remains to be studied. Previously, we investigated how modifications of PORCN and WLS result in changes in WNT expression and secretion from cells under stress conditions that are found in the tumor microenvironment (hypoxia, oxidative stress, endoplasmic reticulum (ER) stress). The mRNA and protein expression of both PORCN and WLS were notably altered with treatments in human colon cancer (HCT116) cells and human intestinal epithelial (HIEC-6) cells. Our results demonstrated significant changes in expression, which led us to investigate the role of different transcription factors during stresses including (GRP78, HIF1α, NFE2L1, NFEL2L2 and MT1). These transcription factors were altered both at levels of the translation and transcription, when overexpressed by PORCN, WLS and WNT3A. WNT and PORCN levels significantly increased at translation and transcriptional levels when overexpressed by PORCN, WLS and WNT3A. WNT and PORCN undergo palmitoyleation; a modification implicated in cancer cell signalling. The inhibition of palmitoyleation by 2-bromohexdecanoic acid (2-BHDA) resulted in a decrease in the modified forms of PORCN in HCT116 cells. Furthermore, the data showed that palmitoyleation plays an essential role in the expression of WNT proteins; specifically, inhibiting WNT3A and decreasing WLS protein expression in HCT116 cells. However, WLS and WNT3A are modified by N-linked glycosylation. Emerging evidence indicates the critical role of glycosylation in tumor aggressiveness, progression, and metastasis. Cell 2BHDA:

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Protein S‐Palmitoylation: advances and challenges in studying a therapeutically important lipid modification

Cited by 67 publications

References 162 publications

Protein Lipidation by Palmitate Controls Macrophage Function

Protein Lipidation by Palmitate Controls Macrophage Function

Diversity of Lipid Function in Atherogenesis: A Focus on Endothelial Mechanobiology

Investigating the Role of Porcupine and WNTless: Components of WNT Signalling Pathway in Response to Endoplasmic Reticulum, Oxidative, Hypoxia and Environmental Toxins Stesses

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