Endocytosis of interleukin 2 receptors in human T lymphocytes: distinct intracellular localization and fate of the receptor alpha, beta, and gamma chains.

Hémar, Agnès; Subtil, Agathe; Lieb, Michèle; Morélon, Emmanuel; Hellio, Raymond; Dautry‐Varsat, Alice

doi:10.1083/jcb.129.1.55

Cited by 192 publications

(175 citation statements)

References 64 publications

(93 reference statements)

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“…All three subunits initially colocalize with Tfn-R-loaded endosomes. Whereas the ␤ and ␥ chains are subsequently routed to rab7-positive late endosomes for degradation, the ␣ chain is recycled back to the cell surface via recycling endosomes (Hemar et al, 1995). CCR5 could be recycled in an analogous manner.…”

Section: Discussionmentioning

confidence: 99%

Distinct Mechanisms of Agonist-induced Endocytosis for Human Chemokine Receptors CCR5 and CXCR4

Venkatesan

Rose

Lodge

et al. 2003

MBoC

105

111

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Here we demonstrate that the rate of ligand-induced endocytosis of CCR5 in leukocytes and expression systems is significantly slower than that of CXCR4 and requires prolonged agonist treatment, suggesting that these two receptors use distinct mechanisms. We show that the C-terminal domain of CCR5 is the determinant of its slow endocytosis phenotype. When the C-tail of CXCR4 was exchanged for that of CCR5, the resulting CXCR4-CCR5 (X4-R5) chimera displayed a CCR5-like trafficking phenotype. We found that the palmitoylated cysteine residues in this domain anchor CCR5 to plasma membrane rafts. CXCR4 and a C-terminally truncated CCR5 mutant (CCR5-KRFX) lacking these cysteines are not raft associated and are endocytosed by a clathrin-dependent pathway. Genetic inhibition of clathrin-mediated endocytosis demonstrated that a significant fraction of ligand-occupied CCR5 trafficked by clathrin-independent routes into caveolin-containing vesicular structures. Thus, the palmitoylated C-tail of CCR5 is the major determinant of its raft association and endocytic itineraries, differentiating it from CXCR4 and other chemokine receptors. This novel feature of CCR5 may modulate its signaling potential and could explain its preferential use by HIV for person-to-person transmission of disease. INTRODUCTIONClathrin-mediated endocytosis has been the general paradigm and the most extensively studied mechanism of ligand-induced receptor internalization (Schmid, 1997). However, in recent years, alternative clathrin-independent mechanisms have been described for the uptake of viruses, toxins, and receptors that lack conventional endocytic signals ). Among the latter mechanisms, cholesterol-rich structures called caveolae (Anderson, 1998;Kurzchalia and Parton, 1999) and lipid rafts have been implicated in diverse membrane processes including the assembly of signaling receptor complexes (Simons and Toomre, 2000). Endocytosis of some receptors such as the ␣ subunit of the IL-2 receptor (Tac antigen) and MHC-I, which lack canonical endocytic signals, follow distinct itineraries regulated by the small GTP binding protein, ADP-ribosylation factor 6 (Arf6; Radhakrishna and Donaldson, 1997;Sugita et al., 1999). Clathrin-independent endocytic itineraries are slower than the clathrin-dependent pathway and are functionally relevant in that the long residence time of occupied receptors at the cell surface may enable coupling to multiple signaling pathways.Article published online ahead of print. Mol. Biol. Cell 10.1091/ mbc.E02-11-0714. Article and publication date are available at www.molbiolcell.org/cgi/doi/10.1091/mbc.E02-11-0714. † Corresponding author. E-mail address: aradhana@helix.nih.gov or sv1s@nih.gov. § Present address: INRS-Institut Armand-Frappier, Université du Québec, 531 des Prairies, Laval (Québec), Canada H7V 1B7. Abbreviations used: AOP-RANTES, aminooxypentane-regulated on activation, normal T-cell expressed and secreted; APC, allophycocyanin; Arf6, ADP-ribosylation factor 6; CCV, clathrin-coated vesicles; CHO, Chinese hamster o...

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Section: Discussionmentioning

confidence: 99%

Distinct Mechanisms of Agonist-induced Endocytosis for Human Chemokine Receptors CCR5 and CXCR4

Venkatesan

Rose

Lodge

et al. 2003

MBoC

105

111

View full text Add to dashboard Cite

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“…Several members of the Type I cytokine receptor family have been shown to undergo ligandinduced ubiquitination and internalization [17,[20][21][22][23][24][25]. Perhaps the best characterized of these is the GHR.…”

Section: Discussionmentioning

confidence: 99%

“…For the Type I cytokine receptors, endocytosis and degradation has been best characterized for the growth hormone receptor (GH-R), interleukin-2 receptor (IL-2R), and the erythropoietin receptor (EpoR) [20][21][22][23][24][25]. These receptors all undergo ligand-induced ubiquitination.…”

Section: Introductionmentioning

confidence: 99%

Role of the proteasome in modulating native G-CSFR expression

Kindwall‐Keller

Druhan

et al. 2008

Cytokine

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The granulocyte colony-stimulating factor receptor (G-CSFR) is a critical regulator of granulopoiesis, but the mechanisms controlling its surface expression are poorly understood. Recent studies using transfected cell lines have suggested the activated G-CSFR is routed to the lysosome and not the proteasome. Here, we examined the role of the ubiquitin/proteasome system in regulating G-CSFR surface expression in both ts20 cells that have a temperature-sensitive E1 ubiquitinactivating enzyme and in primary human neutrophils. We show that the G-CSFR is constitutively ubiquitinated, which increases following ligand binding. In the absence of a functional E1 enzyme, ligand-induced internalization of the receptor is inhibited. Pre-treatment of ts20 transfectants with either chloroquine or MG132 inhibited ligand-induced G-CSFR degradation, suggesting a role for both lysosomes and proteasomes in regulating G-CSFR surface expression in this cell line. In neutrophils, inhibition of the proteasome but not the lysosome was found to inhibit internalization/ degradation of the activated G-CSFR. Collectively, these data demonstrate the requirement for a functional ubiquitin/proteasome system in G-CSFR internalization and degradation. Our results suggest a prominent role for the proteasome in physiologic modulation of the G-CSFR, and provide further evidence for the importance of the ubiquitin/proteasome system in the initiation of negative signaling by cytokine receptors.

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“…This observation means that there really was less CD25 on the surface of the IL-2 cultured cells because this particular anti-CD25 monoclonal antibody binds to IL-2R alpha even when IL-2 is already bound to the receptor [36]. In the presence of IL-2, the CD25 IL-2R alpha receptor may be cycling, removing the CD25 protein from the surface of the cell [37]. As expected, the transferrin receptor CD71 was up regulated (Fig.…”

Section: Antigen-independent Culture With Il-15 or Il-2 Induces Phenomentioning

confidence: 99%

Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal

et al. 2006

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The purpose of these studies was to determine the minimal requirements to induce granzyme B, cytotoxic granules and perforin-dependent lytic capacity. To our surprise, both IL-2 and IL-15 induced not only proliferation, but also profound granzyme B and lytic capacity from CD8 + T cells in the absence of antigen or TCR-stimulation. Mouse splenocytes were incubated with mouse r-IL-2 or r-IL-15 for three days, tested by anti-CD3 redirected lysis and examined for intracellular granzyme B and for T cell activation markers. With 10 −8 M IL-2 or IL-15, there was excellent lytic activity at 1:1 effector to target ratios mediated by T cells from wild type but not from perforin-gene-ablated mice, consistent with multiclonal activation. Lower interleukin concentrations induced less lytic activity. Granzyme B was undetectable on day 0, and greatly elevated on day 3 in CD44 hi CD8 + T cells as detected by flow cytometry. Cytokines alone elevated the granzyme B as much as concanavalin A combined with the cytokines. Some ex vivo CD8 + T cells were CD122 + , as were the cultured granzyme B + cells, thus both populations had low affinity receptors for the interleukins. Only some of the activated cells were proliferating as detected by CFSE labeling. When the cytokines were withdrawn, the cells lost lytic activity within 24 hours and then within the next 24 hours, died. Our results suggest that high concentrations of either IL-2 or IL-15 will activate the lytic capacity and granzyme B expression of many T cells and that antigen recognition is not required.

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Endocytosis of interleukin 2 receptors in human T lymphocytes: distinct intracellular localization and fate of the receptor alpha, beta, and gamma chains.

Cited by 192 publications

References 64 publications

Distinct Mechanisms of Agonist-induced Endocytosis for Human Chemokine Receptors CCR5 and CXCR4

Distinct Mechanisms of Agonist-induced Endocytosis for Human Chemokine Receptors CCR5 and CXCR4

Role of the proteasome in modulating native G-CSFR expression

Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal

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