title: Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength.
abstract: The humoral immune response, also called the antibody-mediated immune response, is one of the main adaptive immune systems. The essential micronutrient zinc (Zn) is known to modulate adaptive immune responses, and dysregulated Zn homeostasis leads to immunodeficiency. However, the molecular mechanisms underlying this Zn-mediated modulation are largely unknown. Here, we show that the Zn transporter SLC39A10/ZIP10 plays an important role in B-cell antigen receptor (BCR) signal transduction. Zip10-deficiency in mature B cells attenuated both T-cell-dependent and -independent immune responses in vivo. The Zip10-deficient mature B cells proliferated poorly in response to BCR cross-linking, as a result of dysregulated BCR signaling. The perturbed signaling was found to be triggered by a reduction in CD45R phosphatase activity and consequent hyperactivation of LYN, an essential protein kinase in BCR signaling. Our data suggest that ZIP10 functions as a positive regulator of CD45R to modulate the BCR signal strength, thereby setting a threshold for BCR signaling in humoral immune responses.
authors: Laboratory for Homeostatic Network,Osteoimmunology, Deutsches Rheuma-Forschungszentrum, 10117 Berlin, Germany;
authors: Shintaro
authors: S
authors: Hojyo
authors: Laboratory for Immune Regeneration,Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan;
authors: Tomohiro
authors: T
authors: Miyai
authors: Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan;
authors: Hitomi
authors: H
authors: Fujishiro
authors: Laboratory for Immunotherapy.
authors: Masami
authors: M
authors: Kawamura
authors: Laboratory for Immunogenetics.
authors: Takuwa
authors: T
authors: Yasuda
authors: Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan;
authors: Atsushi
authors: A
authors: Hijikata
authors: Bioscience Research Institute, Amorepacific Corporation Research and Development Center, Yongin 446-729, Republic of Korea;Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo 142-8555, Japan;
authors: Bum-Ho
authors: BH
authors: Bin
authors: Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo 142-8555, Japan;
authors: Tarou
authors: T
authors: Irié
authors: Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo 142-8555, Japan;
authors: Junichi
authors: J
authors: Tanaka
authors: Molecular Neuroimmunology, Institute of Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan; and.
authors: Toru
authors: T
authors: Atsumi
authors: Molecular Neuroimmunology, Institute of Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan; and.
authors: Masaaki
authors: M
authors: Murakami
authors: Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan.
authors: Manabu
authors: M
authors: Nakayama
authors: Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, JapanLaboratory for Integrative Genomics, and.
authors: Osamu
authors: O
authors: Ohara
authors: Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan;
authors: Seiichiro
authors: S
authors: Himeno
authors: Laboratory for Immunogenetics.
authors: Hisahiro
authors: H
authors: Yoshida
authors: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan;
authors: Haruhiko
authors: H
authors: Koseki
authors: Laboratory for Immune Regeneration.
authors: Tomokatsu
authors: T
authors: Ikawa
authors: Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo 142-8555, Japan;
authors: Kenji
authors: K
authors: Mishima
authors: Laboratory for Homeostatic Network,Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo 142-8555, Japan; fukada@rcai.riken.jp.
authors: Toshiyuki
authors: T
authors: Fukada
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D016922:Cellular Senescence / Q000276:immunology; D056724:Immunity, Humoral; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D011947:Receptors, Antigen, B-Cell; C557566:ZIP10 protein, mouse; D017493:Leukocyte Common Antigens; D015032:Zinc
keywords: B lymphocyte; acquired immunity; antigen-presenting cell; germinal center; zinc signaling