Intracellular localization and tissue-specific distribution of human and yeast DHHC cysteine-rich domain-containing proteins

Ohno, Yusuke; Kihara, Akio; Sano, Tomoaki; Igarashi, Yasuyuki

doi:10.1016/j.bbalip.2006.03.010

Cited by 411 publications

(495 citation statements)

References 32 publications

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“…Immunoblotting with anti-DHHC7 antibody shows that this enzyme is expressed in all colorectal cell lines tested ( Figure 2d). As reported by several studies, we confirmed by immunofluorescence that DHHC7 is expressed in the Golgi apparatus 15,23 (Supplementary Figure S2a), thus suggesting that Fas palmitoylation occurs in this vesicular compartment.…”

Section: Resultssupporting

confidence: 89%

“…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.…”

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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: Resultssupporting

confidence: 89%

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confidence: 99%

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

et al. 2014

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“…We exploited a genetically sensitized form of HMR silencing and identified PFA4, a gene that encodes a DHHC (asp-his-his-cys) domain-containing, integral membrane S-palmitoyltransferase of the endoplasmic reticulum (ER) (11,12). The data supported a model in which Pfa4 modulated HM silencing, Sir-complex dynamics, and macromolecular aspects of telomere architecture by palmitoylating the telomere binding protein Rif1.…”

supporting

confidence: 51%

Palmitoylation controls the dynamics of budding-yeast heterochromatin via the telomere-binding protein Rif1

Park¹,

Patterson

Cobb³

et al. 2011

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

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The posttranslational addition of palmitate to cysteines occurs ubiquitously in eukaryotic cells, where it functions in anchoring target proteins to membranes and in vesicular trafficking. Here we show that the Saccharomyces cerevisiae palmitoyltransferase Pfa4 enhanced heterochromatin formation at the cryptic mating-type loci HMR and HML via Rif1, a telomere regulatory protein. Acylated Rif1 was detected in extracts from wild-type but not pfa4Δ mutant cells. In a pfa4Δ mutant, Rif1-GFP dispersed away from foci positioned at the nuclear periphery into the nucleoplasm. Sir3-GFP distribution was also perturbed, indicating a change in the nuclear dynamics of heterochromatin proteins. Genetic analyses indicated that PFA4 functioned upstream of RIF1. Surprisingly, the pfa4Δ mutation had only mild effects on telomeric regulation, suggesting Rif1's roles at HM loci and telomeres were more complexly related than previously thought. These data supported a model in which Pfa4-dependent palmitoylation of Rif1 anchored it to the inner nuclear membrane, influencing its role in heterochromatin dynamics.transcriptional silencing | chromosome architecture

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“…The development of specific inhibitors of PATs is restricted by the high level of conservation among PATs in eukaryotic species and the conserved use of palmitoyl-CoA as a substrate (Ducker et al, 2006). Furthermore, it has been shown that a high level of redundancy exists, so that without targeting all, or at least the majority, of PATs, little effect will probably be observed (Ohno et al, 2006;Roth et al, 2006). The situation is clearly different in T. gondii, where five putative PATs appear to be essential for parasite survival, with the indispensability of TgDHHC7 being experimentally proven by the failure in propagating the mutant with a DiCre excised gene (Frenal et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…As in humans and yeast (Ohno et al, 2006), these DHHCs are targeted to distinct endomembrane compartments, with several of them found in the Golgi apparatus (Table 2). In addition, some enzymes are found at the PM and in the apicomplexan-specific organelles including the IMC and the rhoptries.…”

Section: Enzymes Implicated In Protein Palmitoylationmentioning

confidence: 99%

Emerging roles for protein S-palmitoylation in Toxoplasma biology

Frénal

Kemp

Soldati‐Favre

2014

International Journal for Parasitology

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a b s t r a c tPost-translational modifications are refined, rapidly responsive and powerful ways to modulate protein function. Among post-translational modifications, acylation is now emerging as a widespread modification exploited by eukaryotes, bacteria and viruses to control biological processes. Protein palmitoylation involves the attachment of palmitic acid, also known as hexadecanoic acid, to cysteine residues of integral and peripheral membrane proteins and increases their affinity for membranes. Importantly, similar to phosphorylation, palmitoylation is reversible and is becoming recognised as instrumental for the regulation of protein function by modulating protein interactions, stability, folding, trafficking and signalling. Palmitoylation appears to play a central role in the biology of the Apicomplexa, regulating critical processes such as host cell invasion which is vital for parasite survival and dissemination. The recent identification of over 400 palmitoylated proteins in Plasmodium falciparum erythrocytic stages illustrates the broad spread and impact of this modification on parasite biology. The main enzymes responsible for protein palmitoylation are multi-membrane protein S-acyl transferases harbouring a catalytic Asp-HisHis-Cys (DHHC) motif. A global functional analysis of the repertoire of protein S-acyl transferases in Toxoplasma gondii and Plasmodium berghei has recently been performed. The essential nature of some of these enzymes illustrates the key roles played by this post-translational modification in the corresponding substrates implicated in fundamental processes such as parasite motility and organelle biogenesis. Toward a better understanding of the depalmitoylation event, a protein with palmitoyl protein thioesterase activity has been identified in T. gondii. TgPPT1/TgASH1 is the main target of specific acyl protein thioesterase inhibitors but is dispensable for parasite survival, suggesting the implication of other genes in depalmitoylation. Palmitoylation/depalmitoylation cycles are now emerging as potential novel regulatory networks and T. gondii represents a superb model organism in which to explore their significance.

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Intracellular localization and tissue-specific distribution of human and yeast DHHC cysteine-rich domain-containing proteins

Cited by 411 publications

References 32 publications

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

Palmitoylation controls the dynamics of budding-yeast heterochromatin via the telomere-binding protein Rif1

Emerging roles for protein S-palmitoylation in Toxoplasma biology

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