DHHC palmitoyl transferases: substrate interactions and (patho)physiology

Greaves, Jennifer; Chamberlain, Luke H.

doi:10.1016/j.tibs.2011.01.003

Cited by 287 publications

(346 citation statements)

References 86 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: 82%

“…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.…”

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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: 82%

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confidence: 99%

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

et al. 2014

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“…In fact, the authors note a marked increase in the fraction of vertebrate DHHC enzymes containing predicted PDZ ligands, compared with their invertebrate counterparts. This suggests that the appearance of 'palmitoylatable' sites in AMPA receptor regulators may have been paralleled by an increased capacity to recognise these proteins as palmitoylation substrates.As Thomas and Hayashi discuss, further experiments are required to assess precisely how palmitoylation contributes to higher brain function, and in their article they have focused their attention on a small subset of the several hundred palmitoylated brain proteins [5]. It is not easy to directly test the presented hypothesis.…”

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confidence: 99%

“…A family of over twenty 'DHHC' S-acyltransferases regulate cellular palmitoylation dynamics, and enzymes active against AMPA receptor subunits, PSD95 and GRIP1b, have been identified [2,4,5]. Two DHHC enzymes that are active against GRIP1b use C-terminal PDZ ligands to recognise PDZ domains present in this substrate, a mode of enzymesubstrate recognition that is essential for GRIP1b palmitoylation [4].…”

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Evolving views on protein palmitoylation (Comment on DOI 10.1002/bies.201300076)

Chamberlain

2013

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In their Hypotheses article, Thomas and Hayashi [1] engagingly discuss how the evolutionary acquisition of palmitoylation sites may have provided 'add-ons' that extend the capacity to regulate key neuronal proteins. They argue that this increased regulatory capacity may be an important factor in the development of a more complex nervous system during vertebrate evolution.Palmitoylation is a reversible posttranslational modification involving the attachment of palmitate and other fatty acids to cysteine residues. Several hundred neuronal proteins undergo palmitoylation, including AMPA receptors, which mediate fast excitatory glutamate neurotransmission. AMPA receptor levels at the post-synaptic membrane are an important determinant of synaptic strength and plasticity, and it is argued that additional acquired modes of receptor regulation might represent important adaptations in organisms with more complex nervous systems. AMPA receptor subunits are modified by palmitoylation at two sites, the cytosolic boundary of the second transmembrane domain and the cytosolic C-terminus [2]; palmitoylation at both sites regulates cell surface expression, albeit by different mechanisms [2]. Furthermore, palmitoylation also modulates the targeting of proteins that regulate AMPA receptor localisation and function. PSD95 acts as a molecular anchor for several proteins present at post-synaptic regions, and it indirectly tethers AMPA receptors. Preventing the palmitoylation of two cysteines in the N-terminus of PSD95 leads to a loss of this protein from synapses, accompanied by reduced synaptic expression of AMPA receptors [3]. Palmitoylation also controls the targeting of GRIP1b to dendritic endosomes, where it regulates the distribution of AMPA receptors between endosomes and the cell surface [4]. Thomas and Hayashi report that known palmitoylation sites in AMPA receptors, PSD95 and GRIP1b, are mainly restricted to vertebrates. Thus, the acquisition of a multi-layered palmitoylation control of AMPA receptor localisation and function might represent a key adaptation contributing to higher brain function.The authors complement their analysis of palmitoylation substrates by examining palmitoylation enzymes. A family of over twenty 'DHHC' S-acyltransferases regulate cellular palmitoylation dynamics, and enzymes active against AMPA receptor subunits, PSD95 and GRIP1b, have been identified [2,4,5]. Two DHHC enzymes that are active against GRIP1b use C-terminal PDZ ligands to recognise PDZ domains present in this substrate, a mode of enzymesubstrate recognition that is essential for GRIP1b palmitoylation [4]. Although the mechanisms underlying PSD95 recognition by DHHC enzymes have not been delineated, there may be a similar recognition of the PSD95 PDZ domains. If key neuronal proteins have acquired palmitoylation sites during evolution, have the DHHC enzymes acquired the ability to recognise these proteins? In fact, the authors note a marked increase in the fraction of vertebrate DHHC enzymes containing predicted PDZ ligands, compar...

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S‐palmitoylation regulates innate immune signaling pathways: molecular mechanisms and targeted therapies

2023

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S‐palmitoylation is a reversible posttranslational lipid modification that targets cysteine residues of proteins and plays critical roles in regulating the biological processes of substrate proteins. The innate immune system serves as the first line of defense against pathogenic invaders and participates in the maintenance of tissue homeostasis. Emerging studies have uncovered the functions of S‐palmitoylation in modulating innate immune responses. In this review, we focus on the reversible palmitoylation of innate immune signaling proteins, with particular emphasis on its roles in the regulation of protein localization, protein stability, and protein–protein interactions. We also highlight the potential and challenge of developing therapies that target S‐palmitoylation or de‐palmitoylation for various diseases.

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DHHC palmitoyl transferases: substrate interactions and (patho)physiology

Cited by 287 publications

References 86 publications

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

Evolving views on protein palmitoylation (Comment on DOI 10.1002/bies.201300076)

S‐palmitoylation regulates innate immune signaling pathways: molecular mechanisms and targeted therapies

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