The intracellular dynamic of protein palmitoylation

Salaün, Christine; Greaves, Jennifer; Chamberlain, Luke H.

doi:10.1083/jcb.201008160

Cited by 310 publications

(328 citation statements)

References 94 publications

(202 reference statements)

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“…We also observe reduced palmitoylation of PLM in hearts from transgenic mice expressing unphosphorylatable PLM compared with wild type littermates (data not shown). As discussed, these post-translational modifications usually oppose each other because they have opposite effects on the membrane association of intracellular regions of proteins (32). However, the NMR structure of serine 68-phosphorylated PLM (43) indicates that phosphorylation increases the mobility of PLM helix 4 (Fig.…”

Section: Position Of the Palmitoylation Sites In Plm-mentioning

confidence: 99%

“…palmitoylation, through increasing the membrane localization of intracellular loops, limits access of protein kinases to nearby phosphorylation sites, and phosphorylation, by repelling intracellular loops from the intracellular face of the lipid bilayer, opposes their membrane recruitment and palmitoylation) (32). Because the phosphorylation sites in PLM lie ϳ25 amino acids from the palmitoylation sites, we investigated the relationship between phosphorylation and palmitoylation of PLM in both ARVM and transfected HEK cells.…”

Section: Volume 286 • Number 41 • October 14 2011mentioning

confidence: 99%

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The Inhibitory Effect of Phospholemman on the Sodium Pump Requires Its Palmitoylation

Tulloch

Howie

Wypijewski

et al. 2011

Journal of Biological Chemistry

110

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Background: Phospholemman regulates the plasmalemmal sodium pump in excitable tissues such as the heart. Results: Phospholemman is palmitoylated at two intracellular cysteines, and this reduces ion transport by the sodium pump. Conclusion: Phospholemman must be palmitoylated to inhibit the sodium pump. Significance: This is a potentially new way to regulate the sodium pump, an enzyme expressed in most eukaryotic cells.

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Section: Position Of the Palmitoylation Sites In Plm-mentioning

confidence: 99%

Section: Volume 286 • Number 41 • October 14 2011mentioning

confidence: 99%

The Inhibitory Effect of Phospholemman on the Sodium Pump Requires Its Palmitoylation

Tulloch

Howie

Wypijewski

et al. 2011

Journal of Biological Chemistry

110

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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.

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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“…Interestingly, protein palmitoylation has been shown to regulate phosphorylation of several proteins. 60,61 However, it remains to be investigated whether CASP6 phosphorylation and palmitoylation regulate each other and whether they work synergistically or independently to regulate CASP6 activation. Thus further studies on the interaction between phosphorylation and palmitoylation of CASP6 are needed.…”

Section: Discussionmentioning

confidence: 99%

Palmitoylation of caspase-6 by HIP14 regulates its activation

et al. 2016

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Caspase-6 (CASP6) has an important role in axonal degeneration during neuronal apoptosis and in the neurodegenerative diseases Alzheimer and Huntington disease. Decreasing CASP6 activity may help to restore neuronal function in these and other diseases such as stroke and ischemia, where increased CASP6 activity has been implicated. The key to finding approaches to decrease CASP6 activity is a deeper understanding of the mechanisms regulating CASP6 activation. We show that CASP6 is posttranslationally palmitoylated by the palmitoyl acyltransferase HIP14 and that the palmitoylation of CASP6 inhibits its activation. Palmitoylation of CASP6 is decreased both in Hip14 −/− mice, where HIP14 is absent, and in YAC128 mice, a model of Huntington disease, where HIP14 is dysfunctional and where CASP6 activity is increased. Molecular modeling suggests that palmitoylation of CASP6 may inhibit its activation via steric blockage of the substrate-binding groove and inhibition of CASP6 dimerization, both essential for CASP6 function. Our studies identify palmitoylation as a novel CASP6 modification and as a key regulator of CASP6 activity.

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The intracellular dynamic of protein palmitoylation

Cited by 310 publications

References 94 publications

The Inhibitory Effect of Phospholemman on the Sodium Pump Requires Its Palmitoylation

The Inhibitory Effect of Phospholemman on the Sodium Pump Requires Its Palmitoylation

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

Palmitoylation of caspase-6 by HIP14 regulates its activation

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