The Palmitoylation Machinery Is a Spatially Organizing System for Peripheral Membrane Proteins

Rocks, Oliver; Gerauer, Marc; Vartak, Nachiket; Koch, Sebastian; Huang, Zhiping; Pechlivanis, Markos; Kuhlmann, Jürgen; Brunsveld, Luc; Chandra, Anchal; Ellinger, Bernhard; Waldmann, Herbert; Bastiaens, Philippe I. H.

doi:10.1016/j.cell.2010.04.007

Cited by 404 publications

(482 citation statements)

References 56 publications

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“…Whereas several studies concluded that particular DHHC(s) palmitoylate defined substrates, 14,16,23,30 it was postulated that any Golgi-resident DHHC can palmitoylate the palmitoylable peripheral membrane proteins. 31 Our results argue for some specificity of DHHC proteins toward their substrate, as only knockdown of DHHC7 really impacts Fas palmitoylation. However, residual Fas palmitoylation is detected upon DHHC7 silencing, which can be attributed to incomplete DHHC7 knockdown or to additional minor contribution from other DHHC proteins that the sensitivity of our assay did not allow to identify.…”

Section: Discussionmentioning

confidence: 72%

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: Discussionmentioning

confidence: 72%

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

et al. 2014

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“…We and others have established that the membrane trafficking of N-Ras and H-Ras, which are palmitoylated, differs substantially from that of K-Ras4B, in that N-Ras and H-Ras access the PM through the cytoplasmic surface of the Golgi apparatus, whereas K-Ras4B does not associate with the Golgi (5). The protein palmitoylacyltransferase that modifies N-Ras and H-Ras, DHHC9/GCP16, resides on the Golgi (28), and these Ras isoforms engage in a cycle of palmitoylation/depalmitoylation that takes them to and from the PM (29)(30)(31). At steady state, GFP-N-Ras and GFP-H-Ras can clearly be observed on the Golgi in a variety of cultured cells (5).…”

Section: Discussionmentioning

confidence: 99%

K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif

Tsai

Lopes

Zhou

et al. 2015

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

195

256

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The two products of the KRAS locus, K-Ras4A and K-Ras4B, are encoded by alternative fourth exons and therefore, possess distinct membrane-targeting sequences. The common activating mutations occur in exons 1 or 2 and therefore, render both splice variants oncogenic. K-Ras4A has been understudied, because it has been considered a minor splice variant. By priming off of the splice junction, we developed a quantitative RT-PCR assay for K-Ras4A and K-Ras4B message capable of measuring absolute amounts of the two transcripts. We found that K-Ras4A was widely expressed in 30 of 30 human cancer cell lines and amounts equal to K-Ras4B in 17 human colorectal tumors. Using splice variant-specific antibodies, we detected K-Ras4A protein in several tumor cell lines at a level equal to or greater than that of K-Ras4B. In addition to the CAAX motif, the C terminus of K-Ras4A contains a site of palmitoylation as well as a bipartite polybasic region. Although both were required for maximal efficiency, each of these could independently deliver K-Ras4A to the plasma membrane. Thus, among four Ras proteins, K-Ras4A is unique in possessing a dual membrane-targeting motif. We also found that, unlike K-Ras4B, K-Ras4A does not bind to the cytosolic chaperone δ-subunit of cGMP phosphodiesterase type 6 (PDE6δ). We conclude that efforts to develop anti–K-Ras drugs that interfere with membrane trafficking will have to take into account the distinct modes of targeting of the two K-Ras splice variants.

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“…Tetrahymena, Toxoplasma, and Plasmodium possess 38, 18, and 12 predicted PATs, respectively. PATs reside in different tissues and sub-cellular localizations and are thought to direct the recruitment of proteins to specific membranes: for example, Vac8 to vacuole membrane in yeast (24), RAS2 in mammalian cell lines to the plasma membrane (25), and TgARO in T. gondii to the rhoptry membrane (26,27). A localization map of PATs in T. gondii and P. berghei was recently established, with two PATs found to localize to the IMC (26,28).…”

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confidence: 99%

The Role of Palmitoylation for Protein Recruitment to the Inner Membrane Complex of the Malaria Parasite

Wetzel

Herrmann

Swapna

et al. 2015

Journal of Biological Chemistry

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Background: Recruitment of peripheral proteins to the inner membrane complex (IMC) of the malaria parasite can be mediated by N-terminal acylation. Results: Characterization of substrate determinants and identification of an IMC-localized palmitoyl acyltransferase PfDHHC1. Conclusion: Residues close to palmitoylation sites interfere with specific IMC recruitment. PfDHHC1 represents an apicomplexan-specific PAT. Significance: Dissection of palmitoylation for protein recruitment to the inner membrane complex in P. falciparum.

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The Palmitoylation Machinery Is a Spatially Organizing System for Peripheral Membrane Proteins

Cited by 404 publications

References 56 publications

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif

The Role of Palmitoylation for Protein Recruitment to the Inner Membrane Complex of the Malaria Parasite

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