Multiple Palmitoyltransferases Are Required for Palmitoylation-dependent Regulation of Large Conductance Calcium- and Voltage-activated Potassium Channels

Tian, Lijun; McClafferty, Heather; Jeffries, Owen; Shipston, Michael J.

doi:10.1074/jbc.m110.137802

Cited by 71 publications

(88 citation statements)

References 34 publications

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“…16,[23][24][25] We show that endogenous DHHC7 constitutively co-immunoprecipitates with endogenous Fas in SW480 LacZ cell lysate ( Figure 2e). As expected, this DHHC7/Fas association is enhanced when Fas WT is overexpressed (Figure 2e).…”

Section: Resultsmentioning

confidence: 81%

“…Indeed, a number of studies showed that palmitoylated proteins can assemble with their cognate DHHC during the palmitoylation process. 16,[23][24][25] We previously demonstrated that the TRAIL receptor DR4 is also palmitoylated, this palmitoylation contributing to DR4 ability to induce cell death by targeting DR4 to specific membrane nanodomains. 32 Interestingly, a recent report links DHHC3, the closest DHHC member of DHHC7, as a DR4 interacting protein by a two-hybrid screen.…”

Section: Discussionmentioning

confidence: 99%

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Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

et al. 2014

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The death receptor Fas undergoes a variety of post-translational modifications including S-palmitoylation. This protein acylation has been reported essential for an optimal cell death signaling by allowing both a proper Fas localization in cholesterol and sphingolipid-enriched membrane nanodomains, as well as Fas high-molecular weight complexes. In human, S-palmitoylation is controlled by 23 members of the DHHC family through their palmitoyl acyltransferase activity. In order to better understand the role of this post-translational modification in the regulation of the Fas-mediated apoptosis pathway, we performed a screen that allowed the identification of DHHC7 as a Fas-palmitoylating enzyme. Indeed, modifying DHHC7 expression by specific silencing or overexpression, respectively, reduces or enhances Fas palmitoylation and DHHC7 co-immunoprecipitates with Fas. At a functional level, DHHC7-mediated palmitoylation of Fas allows a proper Fas expression level by preventing its degradation through the lysosomes. Indeed, the decrease of Fas expression obtained upon loss of Fas palmitoylation can be restored by inhibiting the lysosomal degradation pathway. We describe the modification of Fas by palmitoylation as a novel mechanism for the regulation of Fas expression through its ability to circumvent its degradation by lysosomal proteolysis. Cell Death and Differentiation (2015) We demonstrated that Fas and FasL are constitutively modified by S-palmitoylation, a reversible post-translational modification that consists in the addition of a palmitic acid on the cysteine residue through a thiol linkage. [8][9][10] The palmitoylation of a protein can affect its interactions with its surrounding membrane lipids and proteins, therefore impacting certain properties such as association with specific membrane domains, trafficking between cell compartments or stability. [11][12][13] The palmitoylation reaction is catalyzed by the conserved DHHC (aspartate-histidine-histidine-cysteine) family of enzymes, which are characterized by the specific DHHC motif required for the palmitoyl acyltransferase (PAT) activity. 14 In human, the 23 members of the DHHC family described are localized to the distinct intracellular membrane compartments, mainly the Golgi apparatus and the endoplasmic reticulum where palmitoylation likely occurs. 14,15 Since their discovery in 2002, increasing numbers of DHHC-substrate pairs have been identified allowing a deeper comprehension of palmitoylation regulation. 16 Fas palmitoylation occurs on an intracellular cysteine adjacent to the transmembrane domain (cysteine 199 in human) and is critical for its ability to trigger cell death. 8,9 At the molecular level, we and others already reported that the pro-death role of Fas palmitoylation relies on (i) the formation of supramolecular Fas aggregates 9 and (ii) Fas targeting in nanodomains enriched in cholesterol and glycosphingolipids, which is a prerequisite for proper activation of Fas-induced cell death. 8,[17][18][19][20][21] In these domains and upon FasL...

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Section: Resultsmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

et al. 2014

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“…Calnexin that is a major ER chaperone involved in glycoprotein folding was reported to be palmitoylated by DHHC6 with no requirement of other cofactors [68]. It seems that requirement of cofactors for PAT activity is not dependent on DHHC proteins rather it may depend on the substrates because STREX channel palmitoylation by DHHC9 [88] and calnexin palmitoylation by DHHC6 [68] do not require any cofactors for their PAT activity. More pairs of different DHHCs and their substrates are summarized in Table 2.…”

Section: Dhhc Patsubstrate Pairsmentioning

confidence: 94%

“…Further, crosstalk among these PTMs has also been demonstrated to contribute to fine tuning of the regulation of synaptic protein functions [27,260,261]. Knockdown of any DHHCs palmitoylating the alternatively spliced stress-regulated exon (STREX) variant of the intracellular C-terminal domain of the large conductance calcium-and voltage-activated potassium (BK) channels prevented the protein kinase A (PKA)-mediated inhibition of STREX channels [88], providing an evidence for an interplay between palmitoylation and phosphorylation to regulate STREX channels. In addition, a reciprocal control of synaptic targeting of PSD-95 was reported to be mediated by an interplay between palmitoylation and nitrosylation [260].…”

Section: Perspectivesmentioning

confidence: 99%

Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

Cho

Park

2016

Pharmacological Research

107

108

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Posttranslational modifications of proteins are important regulatory processes endowing the proteins functional complexity. Over the last decade, numerous studies have shed light on the roles of palmitoylation, one of the most common lipid modifications, in various aspects of neuronal functions. Major players regulating palmitoylation are the enzymes that mediate palmitoylation and depalmitoylation which are palmitoyl acyltransferases (PATs) and protein thioesterases, respectively. In this review, we will provide and discuss current understandings on palmitoyation/depalmitoylation control mediated by PATs and/or protein thioesterases for neuronal functions in general and also for Alzheimer's disease in particular, and other neurodegenerative diseases such as Huntington's disease, schizophrenia and intellectual disability.

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“…To identify those DHHC isoforms that are expressed in rat cardiac myocytes, we used a quantitative PCR approach similar to one that successfully determined the expression profile of DHHC isoforms in HEK cells (18). mRNA was prepared from four independent rat hearts.…”

Section: Resultsmentioning

confidence: 99%

Substrate recognition by the cell surface palmitoyl transferase DHHC5

Howie

Reilly

Fraser

et al. 2014

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

Self Cite

104

157

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The cardiac phosphoprotein phospholemman (PLM) regulates the cardiac sodium pump, activating the pump when phosphorylated and inhibiting it when palmitoylated. Protein palmitoylation, the reversible attachment of a 16 carbon fatty acid to a cysteine thiol, is catalyzed by the Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases. The cell surface palmitoyl acyltransferase DHHC5 regulates a growing number of cellular processes, but relatively few DHHC5 substrates have been identified to date. We examined the expression of DHHC isoforms in ventricular muscle and report that DHHC5 is among the most abundantly expressed DHHCs in the heart and localizes to caveolin-enriched cell surface microdomains. DHHC5 coimmunoprecipitates with PLM in ventricular myocytes and transiently transfected cells. Overexpression and silencing experiments indicate that DHHC5 palmitoylates PLM at two juxtamembrane cysteines, C40 and C42, although C40 is the principal palmitoylation site. PLM interaction with and palmitoylation by DHHC5 is independent of the DHHC5 PSD-95/Discslarge/ZO-1 homology (PDZ) binding motif, but requires a ∼120 amino acid region of the DHHC5 intracellular C-tail immediately after the fourth transmembrane domain. PLM C42A but not PLM C40A inhibits the Na pump, indicating PLM palmitoylation at C40 but not C42 is required for PLM-mediated inhibition of pump activity. In conclusion, we demonstrate an enzyme-substrate relationship for DHHC5 and PLM and describe a means of substrate recruitment not hitherto described for this acyltransferase. We propose that PLM palmitoylation by DHHC5 promotes phospholipid interactions that inhibit the Na pump.phospholemman | sodium pump | palmitoylation | DHHC | ion transport P rotein palmitoylation, the reversible attachment of a 16 carbon fatty acid to a cysteine thiol via a thioester bond, is catalyzed by Asp-His-His-Cys motif-containing palmitoyl acyltransferases (DHHC-PATs); there are 23 human isoforms (1). These zinc-finger-containing enzymes typically have four transmembrane (TM) domains, with a conserved ∼50 amino acid cysteine-rich cytosolic core located between TM2 and -3, which contains a conserved DHHC motif, the active site. In contrast, the intracellular amino and carboxyl termini are poorly conserved, and likely contribute to DHHC isoform substrate selectivity (1). DHHC-PATs are expressed throughout the secretory pathway, but DHHC5 is widely recognized as one of very few cell-surfacelocalized PATs (2, 3). The final four amino acids of DHHC5 form a canonical class II PSD-95/Discs-large/ZO-1 homology (PDZ) binding motif, which interacts with postsynaptic density protein 95 (PSD-95) (2), although PSD-95 is not itself a DHHC5 substrate.An appreciation is now growing that protein palmitoylation turns over rapidly (in minutes) for certain proteins (4-8). For example, dynamic surface membrane protein palmitoylation by DHHC5 underlies a novel form of endocytosis, massive endocytosis (MEND), in which up to 70% of the cell surface membrane is internalized (7, 8). Calci...

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Multiple Palmitoyltransferases Are Required for Palmitoylation-dependent Regulation of Large Conductance Calcium- and Voltage-activated Potassium Channels

Cited by 71 publications

References 34 publications

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

Substrate recognition by the cell surface palmitoyl transferase DHHC5

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