Nutrient-Dependent Changes of Protein Palmitoylation: Impact on Nuclear Enzymes and Regulation of Gene Expression

Spinelli, Matteo; Fusco, Salvatore; Grassi, Claudio

doi:10.3390/ijms19123820

Cited by 29 publications

(28 citation statements)

References 147 publications

(172 reference statements)

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“…In cells, palmitoylation of viral membrane proteins facilitate membrane fusion by SARS-CoV and some IAV strains [ 34 , 35 ]. Although the mechanism has not been elucidated, an increase of palmitoylation of some proteins in obese mice suggests an alteration in this pathway [ 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of obesity and SARS-CoV-2 infection: implications for host defence - a living review

Richter

Alrubayyi

Crespo

et al. 2021

Oxford Open Immunology

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The role of obesity in the pathophysiology of respiratory virus infections has become particularly apparent during the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, where obese patients are twice as likely to suffer from severe coronavirus disease 2019 (COVID-19) than healthy weight individuals. Obesity results in disruption of systemic lipid metabolism promoting a state of chronic low-grade inflammation. However, it remains unclear how these underlying metabolic and cellular processes promote severe SARS-CoV-2 infection. Emerging SARS-CoV-2 data and studies of influenza A virus (IAV) show that viruses can further subvert the host’s altered lipid metabolism and exploit obesity-induced alterations in immune cell metabolism and function to promote chronic inflammation and viral propagation. In this review, we outline the systemic metabolic and immune alterations underlying obesity and discuss how these baseline alterations impact the immune response and disease pathophysiology. A better understanding of the immuno-metabolic landscape of obese patients may aid better therapies and future vaccine design.

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Section: Introductionmentioning

confidence: 99%

Impact of obesity and SARS-CoV-2 infection: implications for host defence - a living review

Richter

Alrubayyi

Crespo

et al. 2021

Oxford Open Immunology

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“…This study also showed that overexpression of a non-acylated CD36 mutant in the liver of mice protected against NASH development, implicating CD36 S-acylation in the pathogenesis of this disease. In this regard, dietary lipids, insulin signaling, and ethanol metabolism can alter the palmitoylome (57)(58)(59)(60). For instance, feeding of a high-fat diet (~60% calories from saturated FAs) was associated with hyper-palmitoylation and dysregulation of AMPA glutamate receptor subunit GluA1 in the brain (60).…”

Section: Discussionmentioning

confidence: 99%

S-acylation modulates the function of the apical sodium-dependent bile acid transporter in human cells

Ticho

Malhotra

Manzella

et al. 2020

Journal of Biological Chemistry

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The ileal apical sodium-dependent bile acid transporter (ASBT) is crucial for the enterohepatic circulation of bile acids. ASBT function is rapidly regulated by several posttranslational modifications. One reversible posttranslational modification is S-acylation, involving the covalent attachment of fatty acids to cysteine residues in proteins. However, whether S-acylation affects ASBT function and membrane expression has not been determined. Using the acyl resin-assisted capture method, we found that the majority of ASBT (∼80%) was S-acylated in ileal brush border membrane vesicles from human organ donors, as well as in HEK293 cells stably transfected with ASBT (2BT cells). Metabolic labeling with alkyne–palmitic acid (100 μm for 15 h) also showed that ASBT is S-acylated in 2BT cells. Incubation with the acyltransferase inhibitor 2-bromopalmitate (25 μm for 15 h) significantly reduced ASBT S-acylation, function, and levels on the plasma membrane. Treatment of 2BT cells with saturated palmitic acid (100 μm for 15 h) increased ASBT function, whereas treatment with unsaturated oleic acid significantly reduced ASBT function. Metabolic labeling with alkyne–oleic acid (100 μm for 15 h) revealed that oleic acid attaches to ASBT, suggesting that unsaturated fatty acids may decrease ASBT's function via a direct covalent interaction with ASBT. We also identified Cys-314 as a potential S-acylation site. In conclusion, these results provide evidence that S-acylation is involved in the modulation of ASBT function. These findings underscore the potential for unsaturated fatty acids to reduce ASBT function, which may be useful in disorders in which bile acid toxicity is implicated.

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“…Differences in the palmitoylation of proteins involved in fat and carbohydrate transport and signalling may compromise digestion. Articles reviewing the biological effects of protein palmitoylation have anticipated a functional role in lipid and glucose metabolism 49 , 50 , though ZDHHC6 is not currently implicated. ZDHHC6 localises in the endoplasmic reticulum and is reported to be involved in the palmitoylation of five protein targets 51 – 56 .…”

Section: Discussionmentioning

confidence: 99%

A large deletion on CFA28 omitting ACSL5 gene is associated with intestinal lipid malabsorption in the Australian Kelpie dog breed

O’Brien

Beijerink

Sansom³

et al. 2020

Sci Rep

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Inborn errors of metabolism are genetic conditions that can disrupt intermediary metabolic pathways and cause defective absorption and metabolism of dietary nutrients. In an Australian Kelpie breeding population, 17 puppies presented with intestinal lipid malabsorption. Juvenile dogs exhibited stunted postnatal growth, steatorrhea, abdominal distension and a wiry coat. Using genome-wide association analysis, an associated locus on CFA28 (Praw = 2.87E−06) was discovered and validated in a closely related population (Praw = 1.75E−45). A 103.3 kb deletion NC_006610.3CFA28:g.23380074_23483377del, containing genes Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5) and Zinc Finger DHHC-Type Containing 6 (ZDHHC6), was characterised using whole transcriptomic data. Whole transcriptomic sequencing revealed no expression of ACSL5 and disrupted splicing of ZDHHC6 in jejunal tissue of affected Kelpies. The ACSL5 gene plays a key role in long chain fatty acid absorption, a phenotype similar to that of our affected Kelpies has been observed in a knockout mouse model. A PCR-based diagnostic test was developed and confirmed fully penetrant autosomal recessive mode of inheritance. We conclude the structural variant causing a deletion of the ACSL5 gene is the most likely cause for intestinal lipid malabsorption in the Australian Kelpie.

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Nutrient-Dependent Changes of Protein Palmitoylation: Impact on Nuclear Enzymes and Regulation of Gene Expression

Cited by 29 publications

References 147 publications

Impact of obesity and SARS-CoV-2 infection: implications for host defence - a living review

Impact of obesity and SARS-CoV-2 infection: implications for host defence - a living review

S-acylation modulates the function of the apical sodium-dependent bile acid transporter in human cells

A large deletion on CFA28 omitting ACSL5 gene is associated with intestinal lipid malabsorption in the Australian Kelpie dog breed

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