Arrestins Block G Protein-coupled Receptor-mediated Apoptosis

Revankar, Chetana M.; Vines, Charlotte M.; Cimino, Daniel F.; Prossnitz, Eric R.

doi:10.1074/jbc.m402121200

Cited by 119 publications

(115 citation statements)

References 41 publications

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“…With the V2 Vasopressin receptor, arrestins prevent recycling by trafficking the receptor to the lysosome (21). In contrast, while the FPR does not use arrestins to mediate receptor internalization (80), we have shown that the FPR uses arrestins to regulate receptor recycling (20) and prevent GPCR-mediated apoptosis (81). In these studies, arrestins form distinct small clusters with the GPCRs during internalization and trafficking.…”

Section: Discussionmentioning

confidence: 85%

Arrestin 3 Mediates Endocytosis of CCR7 following Ligation of CCL19 but Not CCL21

Byers

Calloway

Shannon

et al. 2008

The Journal of Immunology

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Internalization of ligand bound G protein-coupled receptors, an important cellular function that mediates receptor desensitization, takes place via distinct pathways, which are often unique for each receptor. The C-C chemokine receptor (CCR7) G protein-coupled receptor is expressed on naive T cells, dendritic cells, and NK cells and has two endogenous ligands, CCL19 and CCL21. Following binding of CCL21, 21 ± 4% of CCR7 is internalized in the HuT 78 human T cell lymphoma line, while 76 ± 8% of CCR7 is internalized upon binding to CCL19. To determine whether arrestins mediated differential internalization of CCR7/CCL19 vs CCR7/CCL21, we used small interfering RNA (siRNA) to knock down expression of arrestin 2 or arrestin 3 in HuT 78 cells. Independent of arrestin 2 or arrestin 3 expression, CCR7/CCL21 internalized. In contrast, following depletion of arrestin 3, CCR7/CCL19 failed to internalize. To examine the consequence of complete loss of both arrestin 2 and arrestin 3 on CCL19/CCR7 internalization, we examined CCR7 internalization in arrestin 2−/−/arrestin 3−/− murine embryonic fibroblasts. Only reconstitution with arrestin 3-GFP but not arrestin 2-GFP rescued internalization of CCR7/CCL19. Loss of arrestin 2 or arrestin 3 blocked migration to CCL19 but had no effect on migration to CCL21. Using immunofluorescence microscopy, we found that arrestins do not cluster at the membrane with CCR7 following ligand binding but cap with CCR7 during receptor internalization. These are the first studies that define a role for arrestin 3 in the internalization of a chemokine receptor following binding of one but not both endogenous ligands.

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Section: Discussionmentioning

confidence: 85%

Arrestin 3 Mediates Endocytosis of CCR7 following Ligation of CCL19 but Not CCL21

Byers

Calloway

Shannon

et al. 2008

The Journal of Immunology

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“…In contrast to the monomeric G-protein signaling, whose fundamental role in the regulation of apoptosis is well established in higher and lower eukaryotes (53,65,80), the role of heterotrimeric G-protein signaling in the induction of apoptosis has been implicated only recently for higher eukaryotes (36,60). Thus far, the pathways involved are still poorly understood, and no evidence has been presented for yeasts or filamentous fungi.…”

Section: Discussionmentioning

confidence: 96%

Antifungal Protein PAF Severely Affects the Integrity of the Plasma Membrane ofAspergillus nidulansand Induces an Apoptosis-Like Phenotype

Leiter¹,

Szappanos

Oberparleiter

et al. 2005

Antimicrob Agents Chemother

154

142

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The small, basic, and cysteine-rich antifungal protein PAF is abundantly secreted into the supernatant by the ␤-lactam producer Penicillium chrysogenum. PAF inhibits the growth of various important plant and zoopathogenic filamentous fungi. Previous studies revealed the active internalization of the antifungal protein and the induction of multifactorial detrimental effects, which finally resulted in morphological changes and growth inhibition in target fungi. In the present study, we offer detailed insights into the mechanism of action of PAF and give evidence for the induction of a programmed cell death-like phenotype. We proved the hyperpolarization of the plasma membrane in PAF-treated Aspergillus nidulans hyphae by using the aminonaphtylethenylpyridinium dye di-8-ANEPPS. The exposure of phosphatidylserine on the surface of A. nidulans protoplasts by Annexin V staining and the detection of DNA strand breaks by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) gave evidence for a PAF-induced apoptotic-like mechanism in A. nidulans. The localization of reactive oxygen species (ROS) by dichlorodihydrofluorescein diacetate and the abnormal cellular ultrastructure analyzed by transmission electron microscopy suggested that ROS-elicited membrane damage and the disintegration of mitochondria played a major role in the cytotoxicity of PAF. Finally, the reduced PAF sensitivity of A. nidulans strain FGSC1053, which carries a dominant-interfering mutation in fadA, supported our assumption that G-protein signaling was involved in PAF-mediated toxicity.A large number of small, basic, cysteine-rich antimicrobial proteins are produced by organisms throughout all kingdoms. They display a great variety in their primary structure, in species specificity, and in the mechanism of action.Few ascomycetes secrete strongly related antifungal proteins, which do not show any sequence homology with other antimicrobial proteins, but most of these proteins exhibit structural similarities (46): a net positive charge and numerous cysteine residues that are involved in disulfide bond formation. These properties contribute to a compact tertiary structure and a high stability against environmental impact and finally support the model of a membrane-disturbing nature. The antifungal protein PAF from P. chrysogenum and AFP from A. giganteus are the two most intensively studied peptides in the group of antifungals from ascomycetes, but the information available on their exact mechanism of action is still rather limited (32,55,68,69). PAF inhibits the growth of various important plant pathogenic and zoopathogenic filamentous fungi, e.g., Aspergillus fumigatus, A. niger, A. nidulans, and Botrytis cinerea. Previous studies revealed the induction of multifactorial detrimental effects on target organisms that include growth inhibition, reduction of cellular metabolism, severe changes in hyphal morphology, increased K ϩ efflux, and the generation of intracellular reactive oxygen species (ROS) (32, 48). PAF was found to...

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“…However, previous studies showing that CXCL12, but not gp120, activates the PI3K/ AKT pathway (Khan et al, 2004) support this hypothesis. In addition, studies from other investigators indicate that beta-arrestins (which mediate receptor internalization) are instrumental in the coupling of GPCRs and tyrosine kinases receptors to antiapoptotic pathways, including AKT Povsic et al, 2003;Revankar et al, 2004). Thus, pathways regulated by AKT (such as the Rb/E2F pathway) could be altered as well (Khan et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Human immunodeficiency virus gp120-induced apoptosis of human neuroblastoma cells in the absence of CXCR4 internalization

et al. 2006

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The chemokine receptor CXCR4 functions as human immunodeficiency virus (HIV)-1 coreceptor and is involved in acquired immunodeficiency virus (AIDS) neuropathogenesis. CXCR4 is expressed by most cell types in the brain, including microglia, astrocytes, and neurons. Studies have shown that the HIV envelope protein gp120 binds to neuronal CXCR4 and activates signal transduction pathways leading to apoptosis. However, the natural CXCR4 ligand (CXCL12) has been referred to induce both neuronal survival and death. Here the authors used flow cytometry to determine whether gp120 and CXCL12 differ in their ability to induce CXCR4 internalization in the human neuroblastoma cells SH-SY5Y, which constitutively express CXCR4. As expected, increasing concentration of CXCL12 reduced surface expression of CXCR4 in a time-and concentrationdependent manner. Conversely, gp120 IIIB (monomeric or oligomeric, in presence or absence of soluble CD4) did not change CXCR4 membrane levels. Similar results were obtained in a murine lymphocyte cell line (300-19) stably expressing human CXCR4. Nevertheless, gp120 IIIB was still able to activate intracellular signaling and proapoptotic pathways, via CXCR4. These results show that gp120 IIIB toxicity and signaling do not require CXCR4 internalization in SH-SY5Y cells, and suggest that the viral protein may alter normal CXCR4 trafficking thus, interfering with activation of prosurvival pathways.

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Arrestins Block G Protein-coupled Receptor-mediated Apoptosis

Cited by 119 publications

References 41 publications

Arrestin 3 Mediates Endocytosis of CCR7 following Ligation of CCL19 but Not CCL21

Arrestin 3 Mediates Endocytosis of CCR7 following Ligation of CCL19 but Not CCL21

Antifungal Protein PAF Severely Affects the Integrity of the Plasma Membrane ofAspergillus nidulansand Induces an Apoptosis-Like Phenotype

Human immunodeficiency virus gp120-induced apoptosis of human neuroblastoma cells in the absence of CXCR4 internalization

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