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Following Ligation of CCL19 but Not CCL21 Arrestin 3 Mediates Arrestin 3 Mediates Endocytosis of CCR7 following Ligation of CCL19 but Not CCL21 Melissa A. Byers, Psachal A. Calloway, Laurie Shannon, Heather D. Cunningham, Sarah Smith, Fang Li, Brian C. This information is current as Fassold and Charlotte M. Vines of September 25, 2021. J Immunol 2008; 181:4723-4732; ; doi: 10.4049/jimmunol.181.7.4723 http://www.jimmunol.org/content/181/7/4723 Downloaded from References This article cites 82 articles, 45 of which you can access for free at: http://www.jimmunol.org/content/181/7/4723.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Arrestin 3 Mediates Endocytosis of CCR7 following Ligation of CCL19 but Not CCL211 Melissa A. Byers,* Psachal A. Calloway,* Laurie Shannon,* Heather D. Cunningham,* Sarah Smith,* Fang Li,† Brian C. Fassold,* and Charlotte M. Vines2* 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, Downloaded from 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 reconsti tution 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 http://www.jimmunol.org/ but not both endogenous ligands. The Journal of Immunology, 2008, 181: 4723–4732. protein-coupled receptors (GPCRs)3 are a diverse group then internalized. Two of the four known arrestins, arrestin 2 and of seven transmembrane receptors that are activated by arrestin 3, are expressed ubiquitously in mammalian cells (8–10). G multiple sensory and chemical stimuli including light, Receptor internalization is an important immunological function odors, tastes, chemokines, and neurotransmitters (as reviewed by that controls signaling, which controls immunological responses, Ref. 1). Activation of these receptors by their ligands induces a receptor fate, and receptor desensitization (11). Yet it is unclear conformational change, which leads to activation of distinct down- how distinct receptors are shuttled to the necessary internalization by guest on September 25, 2021 stream signaling events (2–4). Following activation by agonist machinery to differentially control the signaling and fate of each binding, the GPCRs couple to heterotrimeric GTP-binding (G) internalized receptor. proteins triggering an exchange of GDP for GTP on the G␣-sub- Arrestins can regulate GPCR internalization, degradation and/or unit and the resultant release of the ␣ subunit from the ␤/␥-dimer recycling. Arrestin binding can block association of G proteins (5). These subunits can regulate numerous effectors including ad- with phosphorylated GPCRs and thus plays an important role in ␤ enylyl cyclase and phospholipase C (6, 7). The receptor is then phosphorylation-dependent desensitization (9, 12). For instance, phosphorylated at its C terminus, which provides a substrate for arrestins mediate internalization of the ␤2 adrenergic receptor (10, ␤ high affinity binding by arrestin 2 (also known as -arrestin 1) 13). Arrestins can also serve as adaptors between the receptors and ␤ and/or arrestin 3 (also known as -arrestin 2), and the receptor is the endocytic machinery. In such cases, arrestin binding targets activated receptors to clathrin-coated pits via interactions with *Department of Microbiology, Molecular Genetics and Immunology, The University clathrin, the clathrin adaptor AP-2, and the intracellular transport of Kansas Medical Center, Kansas City, KS 66160; and †The Affiliated Hospital of ATPase N-ethylmaleimide-sensitive factor (14–16). Arrestins can Ningxia Medical College, Yinchuan, Ningxia, People’s Republic of China also regulate other signaling pathways including activating Src, Received for publication October 30, 2007. Accepted for publication July 24, 2008. ERK, and c-Jun N-terminal kinase (17–19). Alternatively, while The costs of publication of this article were defrayed in part by the payment of page the human N-formyl peptide receptor (FPR) does not require ar- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. restins to internalize, arrestins are required for FPR recycling (20). 1 This research was supported by National Institutes of Health Grants 5K22AI060815 In addition, arrestins can mediate trafficking of GPCRs to specific and 2P20RR016443-07 (to C.M.V.). The Flow Cytometry Core is supported by Na- sites in the cell, where the receptors are degraded (8, 21, 22). tional Institutes of Health Grant P20 RR016443 from the National Center for Re- CCR7 is a GPCR that is expressed on B lymphocytes, NK cells, search Resources. Confocal imaging was conducted with staff support within an Na- tional Institute of Child Health and Human Development center supported facility, the and naive and central memory T lymphocytes (23–27). CCR7 is Kansas Intellectual and Developmental Disabilities Research Center imaging core activated by two known endogenous ligands, CCL19 (MIP-3␤, (National Institute of Child Health and Human Development HD 02528). ELC, CK␤-11, Exodus-3) and CCL21 (6Ckine, SLC, TCA4, Ex- 2 Address correspondence and reprint requests to Dr. Charlotte Vines, University of Kansas Medical Center, 3901 Rainbow Boulevard, Wahl Hall West 3025, Kansas odus-2) (26, 28–31). CCL21 is expressed on the luminal side of City, KS 66160. E-mail address: [email protected] high endothelial venules, while both ligands are found within the 3 Abbreviations used in this paper: GPCR, G protein-coupled receptor; FPR, N-formyl stromal region of the T cell-rich lymph node areas (32). The peptide receptor; MEF, murine embryonic fibroblast; sf, serum free; siRNA, small CCL19 ligand is expressed on dendritic cells, and is found at lower interfering RNA. levels in the spleen and lymph nodes than CCL21 (33). The ex- Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 pression of these ligands in different regions of the immune system www.jimmunol.org 4724 DIFFERENTIAL INTERNALIZATION OF CCR7 implies that each ligand might have a unique role in the regulation RPMI 1640/2 mM L-glutamine) (Invitrogen) in a humidified atmosphere of Ϫ/Ϫ Ϫ/Ϫ Ϫ/Ϫ of this system and as a result differentially regulate signaling in T 5% CO2/air at 37°C. The arrestin2 /arrestin3 MEFs (WT and arr2 / Ϫ/Ϫ cells. Indeed, each ligand has been uniquely associated with dif- arr3 ) cell lines were a generous gift from Dr. Robert Lefkowitz (Duke University, Durham, NC). Murine CCR7 was transiently transfected into ferent autoimmune diseases. Although CCL21 has been associated the MEF arr2Ϫ/Ϫ/arr3Ϫ/Ϫ cell lines with Lipofectamine 2000 (Invitrogen) with Sjogren’s syndrome and lymphoproliferative disorders (34– according to the manufacturer’s instructions, with the following modifica- 36), CCL19 has been linked to Crohn’s (37, 38). It is unclear, tion: we halved all recommended amounts. pCDNA3.1 (Invitrogen) vector however, how each of these ligands mediates distinct effects fol- was transfected as the vector control. MEF cell lines were maintained in 10% FBS (HyClone)/90% DMEM supplemented with 2 mM L-glutamine lowing association with CCR7. at 37°C/5% CO2 in a humidified incubator. Cells were certified to be free CCR7 binds CCL19 and CCL21 with equal affinities (30), yet of mycoplasma by Charles River Laboratories. each ligand has distinct signaling pathways and modulation of
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