title: C5L2 is required for C5a-triggered receptor internalization and ERK signaling.
abstract: C5L2 is a receptor that binds to C5a and belongs to the family of G protein-coupled receptors, but its role in physiological C5a-mediated responses remains under debate. Here we show that, like the canonical C5a receptor C5aR, C5L2 plays a pro-inflammatory role in a murine model of acute experimental colitis. We demonstrate that C5L2 physically interacts with C5aR and is required for optimal C5a-mediated C5aR internalization and associated ERK activation. Abrogation of C5a-induced receptor internalization by treatment with the dynamin inhibitor dynasore(TM) impaired C5a-induced MEK and ERK signaling. Although the presence of C5aR alone was sufficient to recruit the scaffold protein β-arrestin1 to the cell membrane in response to C5a stimulation, it was inadequate to mediate AP2 recruitment and subsequent C5aR internalization. Expression of C5L2 allowed normal internalization of C5aR in response to C5a stimulation, followed by normal ERK signaling. Thus, our work reveals an essential role for C5L2 in C5a-triggered, AP2-dependent C5aR internalization and downstream ERK signaling.
authors.affiliation: Institute of Microbiology and Immunology, National Yang Ming University (NYMU), Taipei 11221, Taiwan, ROC.
authors.forename: Wei-Chan
authors.initials: WC
authors.lastname: Hsu
authors.affiliation: Institute of Microbiology and Immunology, National Yang Ming University (NYMU), Taipei 11221, Taiwan, ROC.
authors.forename: Fu-Chen
authors.initials: FC
authors.lastname: Yang
authors.affiliation: Institute of Microbiology and Immunology, National Yang Ming University (NYMU), Taipei 11221, Taiwan, ROC.
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Institute of Microbiology and Immunology, National Yang Ming University (NYMU), Taipei 11221, Taiwan, ROC; Inflammation and Immunity Research Center, National Yang-Ming University, Taipei 11221, Taiwan, ROC; Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan, ROC; Genomics Research Center, Academia Sinica; Institute of Clinical Medicine & Infection and Immunity Center, National Yang-Ming University; Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University; Immunology Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
authors.forename: Shie-Liang
authors.initials: SL
authors.lastname: Hsieh
authors.affiliation: Institute of Microbiology and Immunology, National Yang Ming University (NYMU), Taipei 11221, Taiwan, ROC; Inflammation and Immunity Research Center, National Yang-Ming University, Taipei 11221, Taiwan, ROC. Electronic address: njchen@ym.edu.tw.
authors.forename: Nien-Jung
authors.initials: NJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000276:immunology*; D015936:Complement C5a / Q000276:immunology* / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D034281:Dynamins / Q000037:antagonists & inhibitors; D004705:Endocytosis / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C000594938:C5ar2 protein, mouse; D006835:Hydrazones; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D000071557:beta-Arrestins; D015936:Complement C5a; D016264:Dextran Sulfate; D058539:Phosphatidylinositol 3-Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D034281:Dynamins
keywords: Adaptin 2; C5L2; C5aR; Endocytosis-dependent signaling; Inflammatory bowel disease