Selenoprotein K is required for palmitoylation of CD36 in macrophages: implications in foam cell formation and atherogenesis

Meiler, Svenja; Baumer, Yvonne; Huang, Zhi; Hoffmann, FuKun W.; Fredericks, Gregory J.; Rose, Aaron H.; Norton, Robert L.; Hoffmann, Peter; Boisvert, William A.

doi:10.1189/jlb.1212647

Cited by 57 publications

(41 citation statements)

References 39 publications

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“…Ca 2+ induced with thapsigargin was not altered in Selk-deficient immune cells suggested Selk may affect SOCE through the actions of IP3R. Subsequently, we found that Selk expression was required for the stable expression of a different membrane receptor, the low-density lipoprotein receptor CD36 (17). This study revealed that Selk was required for palmitoylation of CD36, and Selk-deficient macrophages exhibited lower levels of CD36 due to impaired palmitoylation.…”

Section: Significancementioning

confidence: 60%

Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex

Fredericks¹,

Hoffmann²,

Rose³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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134

123

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Calcium (Ca 2+ ) is a secondary messenger in cells and Ca 2+ flux initiated from endoplasmic reticulum (ER) stores via inositol 1,4,5-triphosphate (IP3) binding to the IP3 receptor (IP3R) is particularly important for the activation and function of immune cells. Previous studies demonstrated that genetic deletion of selenoprotein K (Selk) led to decreased Ca 2+ flux in a variety of immune cells and impaired immunity, but the mechanism was unclear. Here we show that Selk deficiency does not affect receptor-induced IP3 production, but Selk deficiency through genetic deletion or low selenium in culture media leads to low expression of the IP3R due to a defect in IP3R palmitoylation. Bioinformatic analysis of the DHHC (letters represent the amino acids aspartic acid, histidine, histidine, and cysteine in the catalytic domain) family of enzymes that catalyze protein palmitoylation revealed that one member, DHHC6, contains a predicted Src-homology 3 (SH3) domain and DHHC6 is localized to the ER membrane. Because Selk is also an ER membrane protein and contains an SH3 binding domain, immunofluorescence and coimmunoprecipitation experiments were conducted and revealed DHHC6/Selk interactions in the ER membrane that depended on SH3/SH3 binding domain interactions. DHHC6 knockdown using shRNA in stably transfected cell lines led to decreased expression of the IP3R and impaired IP3R-dependent Ca 2+ flux. Mass spectrophotometric and bioinformatic analyses of the IP3R protein identified two palmitoylated cysteine residues and another potentially palmitoylated cysteine, and mutation of these three cysteines to alanines resulted in decreased IP3R palmitoylation and function. These findings reveal IP3R palmitoylation as a critical regulator of Ca 2+ flux in immune cells and define a previously unidentified DHHC/Selk complex responsible for this process.I mmune cell activation relies on receptor-mediated increases in cellular calcium (Ca 2+ ) concentrations, which is an indispensable step in proliferation, differentiation, migration, and effector functions during immune responses (1, 2). A rapid influx of Ca 2+ has been shown to be important during the activation of lymphocytes through the T-and B-cell receptors, macrophages through Fcγ receptors, and mast cells through Fce receptors and stimulation of various immune cells through chemokine receptors (3). Engagement of these receptors at the plasma membrane leads to the activation of phosphoinositide-specific phospholipase C, which catalyzes the degradation of phosphatidylinositol-4,5-bisphosphate to generate inositol 1,4,5-triphosphate (IP3) and diacylglycerol (4). IP3 binds to the IP3 receptor (IP3R) in the endoplasmic reticulum (ER) membrane leading to Ca 2+ mobilization from the ER, which is the main Ca 2+ store in immune cells (5). The release of Ca 2+ from the ER lumen to the cytosol causes structural changes and oligomerization of the ER transmembrane protein, stromal interaction molecule 1 (STIM1) (6, 7). These changes allow the cytosolic domain of STIM1 to directly inte...

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Section: Significancementioning

confidence: 60%

Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex

Fredericks¹,

Hoffmann²,

Rose³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

134

123

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“…Furthermore, it contains at least one, possibly two, SH3 recognition sequences that identify it as a probable signaling protein. Recent reports tied SelK to several binding partners, including palmitoyl acyl transferase ZDHHC6 [15] and components of the ER-associated degradation (ERAD) pathway, such as Derlin-1, p97 ATPase, and selenoprotein S (SelS, VIMP) [5,16,17]. Finally, SelK mediates Ca +2 flux in immune cells and is the target of calpain proteases in myeloid cells, a class of proteases involved in regulation of inflammation and immune response [1,18].…”

Section: Introductionmentioning

confidence: 99%

Selenoprotein K form an intermolecular diselenide bond with unusually high redox potential

2014

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Selenoprotein K (SelK) is a membrane protein involved in antioxidant defense, calcium regulation and the ER-associated protein degradation pathway. We found that SelK exhibits a peroxidase activity with a rate that is low but within the range of other peroxidases. Notably, SelK reduced hydrophobic substrates, such as phospholipid hydroperoxides, which damage membranes. Thus, SelK might be involved in membrane repair or related pathways. SelK was also found to contain a diselenide bond — the first intramolecular bond of that kind reported for a selenoprotein. The redox potential of SelK was −257 mV, significantly higher than that of diselenide bonds in small molecules or proteins. Consequently, SelK can be reduced by thioredoxin reductase. These finding are essential for understanding SelK activity and function.

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“…• Anti-viral activity of dendritic cells [294] • Normal function of macrophages [295] • IL-beta-induced NO secretion and activation of caspase 3 in insulin-secreting cells' adipocyte function [296] • Pancreatic beta cell function [297] • Insulin signaling [298] Apoptosis…”

Section: Metabolicmentioning

confidence: 99%

The Deleterious Effects of Oxidative and Nitrosative Stress on Palmitoylation, Membrane Lipid Rafts and Lipid-Based Cellular Signalling: New Drug Targets in Neuroimmune Disorders

Morris¹,

Walder

Puri

et al. 2015

Mol Neurobiol

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Oxidative and nitrosative stress (O&NS) is causatively implicated in the pathogenesis of Alzheimer's and Parkinson's disease, multiple sclerosis, chronic fatigue syndrome, schizophrenia and depression. Many of the consequences stemming from O&NS, including damage to proteins, lipids and DNA, are well known, whereas the effects of O&NS on lipoprotein-based cellular signalling involving palmitoylation and plasma membrane lipid rafts are less well documented. The aim of this narrative review is to discuss the mechanisms involved in lipid-based signalling, including palmitoylation, membrane/lipid raft (MLR) and n-3 polyunsaturated fatty acid (PUFA) functions, the effects of O&NS processes on these processes and their role in the abovementioned diseases. S-palmitoylation is a post-translational modification, which regulates protein trafficking and association with the plasma membrane, protein subcellular location and functions. Palmitoylation and MRLs play a key role in neuronal functions, including glutamatergic neurotransmission, and immune-inflammatory responses. Palmitoylation, MLRs and n-3 PUFAs are vulnerable to the corruptive effects of O&NS. Chronic O&NS inhibits palmitoylation and causes profound changes in lipid membrane composition, e.g. n-3 PUFA depletion, increased membrane permeability and reduced fluidity, which together lead to disorders in intracellular signal transduction, receptor dysfunction and increased neurotoxicity. Disruption of lipid-based signalling is a source of the neuroimmune disorders involved in the pathophysiology of the abovementioned diseases. n-3 PUFA supplementation is a rational therapeutic approach targeting disruptions in lipid-based signalling.

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Selenoprotein K is required for palmitoylation of CD36 in macrophages: implications in foam cell formation and atherogenesis

Cited by 57 publications

References 39 publications

Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex

Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex

Selenoprotein K form an intermolecular diselenide bond with unusually high redox potential

The Deleterious Effects of Oxidative and Nitrosative Stress on Palmitoylation, Membrane Lipid Rafts and Lipid-Based Cellular Signalling: New Drug Targets in Neuroimmune Disorders

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