Palmitoylation of the TRAIL receptor DR4 confers an efficient TRAIL-induced cell death signalling

Rossin, Aurélie; Derouet, Mathieu; Abdel-Sater, Fadi; Hueber, Anne-Odile

doi:10.1042/bj20081212

Cited by 78 publications

(70 citation statements)

References 30 publications

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“…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. 33 Importantly, although the authors do not examine whether DHHC3 could indeed palmitoylate DR4, they demonstrate that DHHC3 is necessary for DR4 targeting to the plasma membrane, thus enhancing TRAIL sensitivity of the cells.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

et al. 2014

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“…Precisely how the modification of DR4 and DR5 by O-linked or N-linked sugars modulates receptor trafficking and/or signaling has yet to be elucidated. Palmitoylation of DRs has been implicated as well in the regulation of extrinsic apoptosis signaling (Chakrabandhu et al, 2007;Feig et al, 2007;Rossin et al, 2009). Fas and DR4 (but not TNFR1 and DR5) were found to be constitutively palmitoylated in cancer cells.…”

Section: Recent Advances In Understanding Apoptosis Initiationmentioning

confidence: 99%

“…Fas and DR4 (but not TNFR1 and DR5) were found to be constitutively palmitoylated in cancer cells. Mutational analysis revealed that DR4 is palmitoylated on a triplet of cysteines located between the receptor's transmembrane and DD region (Rossin et al, 2009). Similar to Fas, inhibition of DR4 palmitoylation affected the ability of DR4 to transduce extrinsic apoptotic signals (Rossin et al, 2009).…”

Section: Recent Advances In Understanding Apoptosis Initiationmentioning

confidence: 99%

“…Mutational analysis revealed that DR4 is palmitoylated on a triplet of cysteines located between the receptor's transmembrane and DD region (Rossin et al, 2009). Similar to Fas, inhibition of DR4 palmitoylation affected the ability of DR4 to transduce extrinsic apoptotic signals (Rossin et al, 2009). Pharmacological inhibition and overexpression studies suggested that palmitoylation of DR4 is required for its localization to lipid rafts and ability to form trimers in the absence of ligand (Rossin et al, 2009).…”

Section: Recent Advances In Understanding Apoptosis Initiationmentioning

confidence: 99%

“…Similar to Fas, inhibition of DR4 palmitoylation affected the ability of DR4 to transduce extrinsic apoptotic signals (Rossin et al, 2009). Pharmacological inhibition and overexpression studies suggested that palmitoylation of DR4 is required for its localization to lipid rafts and ability to form trimers in the absence of ligand (Rossin et al, 2009). Whether the expression levels of specific palmitoyl transferases affect the responsiveness of cancer cells to Apo2L/TRAILinduced apoptosis requires further investigation.…”

Section: Recent Advances In Understanding Apoptosis Initiationmentioning

confidence: 99%

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Palmitoylation in apoptosis

Gong

Xiao

et al. 2023

Journal Cellular Physiology

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Palmitoylation, a critical lipid modification of proteins, is involved in various physiological processes such as altering protein localization, transport, and stability, which perform essential roles in protein function. Palmitoyltransferases are specific enzymes involved in the palmitoylation modification of substrates. S‐palmitoylation, as the only reversible palmitoylation modification, is able to be deacylated by deacyltransferases. As an important mode of programmed cell death, apoptosis functions in the maintenance of organismal homeostasis as well as being associated with inflammatory and immune diseases. Recently, studies have found that palmitoylation and apoptosis have been demonstrated to be related in many human diseases. In this review, we will focus on the role of palmitoylation modifications in apoptosis.

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Palmitoylation of the TRAIL receptor DR4 confers an efficient TRAIL-induced cell death signalling

Cited by 78 publications

References 30 publications

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

New insights into apoptosis signaling by Apo2L/TRAIL

Palmitoylation in apoptosis

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