Essential Role of CD8 Palmitoylation in CD8 Coreceptor Function

Arcaro, Alexandre; Grégoire, Claude; Boucheron, Nicole; Stotz, Sabine H.; Palmer, Ed; Malissen, Bernard; Luescher, Immanuel F.

doi:10.4049/jimmunol.165.4.2068

Cited by 159 publications

(178 citation statements)

References 47 publications

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“…The fast constant has been assigned to their diffusion in disordered membrane domains whereas the slower one to that in the ordered membrane domains [29]. Independent confocal microscopy measurements have also suggested a distribution of both CD8 and TCR molecules between rafts and disordered membrane microdomains: A partial localization of these molecules within lipid raft domains has been observed by us [29] and by other studies [30][31][32][33][34].…”

Section: Lateral Diffusion Of Cd8 and Tcr On Live T-cellsõ Membranes mentioning

confidence: 56%

Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8⁺ T‐cells

Pecht

Gakamsky

2005

FEBS Letters

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The interactions between the TCR and peptides bound to class I MHC encoded molecules (pMHC) and a mechanism for CD8 cooperation in this process are reviewed. Observation of two TCR/CD8 populations with different lateral diffusion rate constants as well as two distinct association phases of class I MHC tetramers ((pMHC) 4 ) with T-cells suggest that the most efficient pMHC-T-cell association route corresponds to a fast tetramer binding to a colocalized CD8/TCR population, which apparently resides within membrane rafts. Thus, ligandcell association starts by pMHC binding to the CD8. This rather fast step promotes pMHC association with CD8-proximal TCRs and thereby enhances the overall association process. The model suggests that this raft-associated CD8-TCR subpopulation is responsible for evoking T-cell activation.

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Section: Lateral Diffusion Of Cd8 and Tcr On Live T-cellsõ Membranes mentioning

confidence: 56%

Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8⁺ T‐cells

Pecht

Gakamsky

2005

FEBS Letters

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“…Palmitoylation involves the post-translational esterification of palmitic acid to a free thiol group of cysteine residues (46). For murine CD8, the CD8␤, but not the CD8␣ chain, was shown to be palmitoylated on a single cysteine located at the boundary of the transmembrane and cytoplasmic domain (8,31). The human CD8␤ chain contains two cysteines in the corresponding region (Fig.…”

Section: Cd8␣␤ But Not Cd8␣␣ Localizes To Lipid Rafts In T Cells-mentioning

confidence: 99%

“…The lipid raft localization of CD4 and CD8 has been shown to enhance T cell activation-induced tyrosine phosphorylation through increasing coreceptor association with Lck and recruiting the TCR to rafts (8,9,31,32). In the case of mouse CD8, targeting to lipid rafts has been demonstrated to depend on palmitoylation of the CD8␤ chain (8,31).…”

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confidence: 99%

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CD8 Raft Localization Is Induced by Its Assembly into CD8αβ Heterodimers, Not CD8αα Homodimers

Pang¹,

Hayday

Bijlmakers

2007

Journal of Biological Chemistry

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The coreceptor CD8 is expressed as a CD8␣␤ heterodimer on major histocompatibility complex class I-restricted TCR␣␤ T cells, and as a CD8␣␣ homodimer on subsets of memory T cells, intraepithelial lymphocytes, natural killer cells, and dendritic cells. Although the role of CD8␣␣ is not well understood, it is increasingly clear that this protein is not a functional homologue of CD8␣␤. On major histocompatibility complex class I-restricted T cells, CD8␣␤ is a more efficient TCR coreceptor than CD8␣␣. This property has for the mouse protein been attributed to the recruitment of CD8␣␤ into lipid rafts, which is dependent on CD8␤ palmitoylation. Here, these divergent distributions of CD8␣␤ and CD8␣␣ are demonstrated for the human CD8 proteins as well. However, although palmitoylation of both CD8␣ and CD8␤ chains was detected, this modification did not contribute to raft localization. In contrast, arginines in the cytoplasmic domain are crucial for raft localization of CD8␤␤. Most strikingly, the assembly of a non-raft localized CD8␤ chain with a non-raft localized CD8␣ chain resulted in raft-localized CD8␣␤ heterodimers. Using chimeric CD8 proteins, this property of the heterodimer was found to be determined by the assembly of CD8␣ and CD8␤ extracellular regions. The presence of two CD8␣ extracellular regions, on the other hand, appears to preclude raft localization. Thus, heterodimer formation and raft association are intimately linked for CD8␣␤. These results emphasize that lipid raft localization is a key feature of human CD8␣␤ that clearly distinguishes it from CD8␣␣.The cell surface glycoprotein CD8 plays an important role in the development and function of MHC 3 class I-restricted T cells. CD8 fulfils its function through interacting via its extracellular domain with MHC class I proteins and via its intracellular domain with the tyrosine kinase Lck (1, 2). An interaction of both the T cell receptor (TCR) and CD8 with MHC proteins enhances the adhesion between the T cell and the antigen-presenting cell. In addition, this dual interaction juxtaposes Lck to the TCR complex, resulting in phosphorylation of CD3 and TCR chains and, thus, the initiation of signaling (3, 4). CD4 performs a corresponding coreceptor role on MHC class IIrestricted T helper cells (5, 6). However, CD8 and CD4 are structurally distinct; CD4 is a monomer, whereas CD8 is a disulfide-linked heterodimer of a CD8␣ and CD8␤ chain. Yet, like CD8, CD4 binds to MHC proteins and interacts with Lck (2, 7). In addition, both proteins have been shown to localize to lipid rafts (8 -11), which are believed to act as key platforms for TCR signaling.The concept of lipid rafts is based on the segregation of lipids into liquid-ordered and liquid-disordered phases (12,13). Raft formation at the plasma membrane is dependent on cholesterol, which tightly packs sphingolipids that contain saturated fatty acids, into a liquid-ordered domain. The phospholipids on the other hand, with at least one unsaturated fatty acid, are in the liquid-disordered phase. Detergent-in...

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“…Subcellular fractionation and isolation of lipid rafts SCLC cells (10 8 ) were lysed in 400 ml of MNE buffer containing 1% Triton X-100, and ultracentrifugation on discontinuous sucrose gradients performed as described (Arcaro et al, 2000) to isolate lipid rafts. Fractionation of SCLC cell into the plama membrane, low-density microsomes and cytosol was performed as previously reported (Arcaro et al, 1998).…”

Section: In Vivo Experimentsmentioning

confidence: 99%

Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling

Pardo²,

et al. 2005

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The impact of the 3-hydroxy-3methylglutaryl CoA reductase inhibitor simvastatin on human small-cell lung cancer (SCLC) cell growth and survival was investigated. Simvastatin profoundly impaired basal and growth factorstimulated SCLC cell growth in vitro and induced apoptosis. SCLC cells treated with simvastatin were sensitized to the effects of the chemotherapeutic agent etoposide. Moreover, SCLC tumour growth in vivo was inhibited by simvastatin. These responses correlated with the inhibition of stem cell factor (SCF)-stimulated activation of extracellular signal-regulated kinase (Erk), protein kinase B (PKB) and ribosomal S6 kinase by simvastatin. Constitutive activation of the Erk pathway was sufficient to rescue SCLC cell from the effects of simvastatin. The drug did not directly affect activation of c-Kit or its localization to lipid rafts, but in addition to its ability to block Ras membrane localization, it selectively downregulated H-Ras protein levels at the post-translational level. Downregulation of either H-or K-Ras by RNA interference (RNAi) did not impair Erk activation by growth factors, whereas an RNAi specific for N-Ras inhibited activation of Erk, PKB and SCLC cell growth. Together our data demonstrate that inhibiting Ras signalling with simvastatin potently disrupts growth and survival in human SCLC cells.

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Essential Role of CD8 Palmitoylation in CD8 Coreceptor Function

Cited by 159 publications

References 47 publications

Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8⁺ T‐cells

Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8⁺ T‐cells

CD8 Raft Localization Is Induced by Its Assembly into CD8αβ Heterodimers, Not CD8αα Homodimers

Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling

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Essential Role of CD8 Palmitoylation in CD8 Coreceptor Function

Cited by 159 publications

References 47 publications

Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8+ T‐cells

Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8+ T‐cells

CD8 Raft Localization Is Induced by Its Assembly into CD8αβ Heterodimers, Not CD8αα Homodimers

Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling

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Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8⁺ T‐cells

Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8⁺ T‐cells