Palmitoylation and the trafficking of peripheral membrane proteins

Chamberlain, Luke H.; Lemonidis, Kimon; Sanchez-Perez, Maria C.; Werno, Martin W.; Gorleku, Oforiwa A; Greaves, Jennifer

doi:10.1042/bst20120243

Cited by 35 publications

(28 citation statements)

References 46 publications

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“…As a result, palmitoylation of proteins is restricted to the cytoplasmic surface of intracellular membrane compartments (Chamberlain et al ., 2013), mainly at the Golgi as a super-reaction center for palmitoylation (Salaun et al ., 2010). Active DHHC proteins have also been detected at post-Golgi membranes, including the plasma membrane of neuronal dendrites (Noritake et al ., 2009) and recycling endosomes and the plasma membrane in PC12 cells (Greaves et al ., 2011).…”

Section: Introductionmentioning

confidence: 99%

Interplay between phosphorylation and palmitoylation mediates plasma membrane targeting and sorting of GAP43

Gauthier-Kemper

Igaev

Sündermann

et al. 2014

MBoC

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Section: Introductionmentioning

confidence: 99%

Interplay between phosphorylation and palmitoylation mediates plasma membrane targeting and sorting of GAP43

Gauthier-Kemper

Igaev

Sündermann

et al. 2014

MBoC

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“…Palmitoylation is a posttranslational modification involving the reversible addition of the 16-carbon fatty acid, palmitate, to cysteine residues through a thioester bond (18), and this modification can facilitate membrane association of proteins or stable expression of transmembrane proteins (19,20). The requirement of Selk for palmitoylation of CD36 and the impaired Ca 2+ flux in Selk-deficient immune cells led us to explore the possibility that the IP3R is palmitoylated in a Selk-dependent manner and that this is required for its stable expression.…”

Section: Significancementioning

confidence: 99%

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.

132

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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“…The active form of palmitic acid for this reaction is palmitoyl-coenzyme A (CoA), and CoA is released when the palmitoyl moeity is added via S-acylation to the target cysteine residue on the target protein. This modification can facilitate membrane association of soluble proteins or influence the stable expression of transmembrane proteins (7,37). When initially considering the possible mechanisms by which SelK may regulate protein palmitoylation, the likelihood of SelK directly catalyzing the addition of palmitoyl fatty acid to target proteins seemed quite low given the lack of any conventional acyltransferase catalytic domain within this selenoprotein.…”

Section: Selkmentioning

confidence: 99%

“…Palmitoylation is a post-translational modification involving the reversible addition of the 16-carbon fatty acid, palmitate, to cysteine residues through a thioester bond (3), and this modification can facilitate membrane association of cytosolic proteins or can promote stable expression of transmembrane proteins (7,37). The requirement of SelK for palmitoylation of CD36 and the impaired Ca 2 + flux in SelKdeficient immune cells led us to form a new hypothesis: The Ca 2 + channel protein in the ER membrane that facilitates Ca 2 + flux in stimulated immune cells, the inositol-1,4,5-triphosphate receptor (IP3R), is palmitoylated in an SelK-dependent manner and this is required for its stable expression.…”

Section: Introductionmentioning

confidence: 99%

Selenoprotein K and Protein Palmitoylation

Fredericks

Hoffmann

2015

Antioxidants & Redox Signaling

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Significance: Selenoprotein K (SelK) is an endoplasmic reticulum (ER) membrane protein, and its expression is sensitive to dietary selenium levels. A recently described role for SelK as a cofactor in catalyzing protein palmitoylation reactions provides an important link between low dietary selenium intake and suboptimal cellular functions that depend on this selenoprotein for palmitoylation. Recent Advances: A recent breakthrough provided insight into the contribution of SelK to calcium (Ca

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Palmitoylation and the trafficking of peripheral membrane proteins

Cited by 35 publications

References 46 publications

Interplay between phosphorylation and palmitoylation mediates plasma membrane targeting and sorting of GAP43

Interplay between phosphorylation and palmitoylation mediates plasma membrane targeting and sorting of GAP43

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

Selenoprotein K and Protein Palmitoylation

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