title: RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells.
abstract: Ras GTPase-activating proteins negatively regulate the Ras/Erk signaling pathway, thereby playing crucial roles in the proliferation, function, and development of various types of cells. In this study, we identified a novel Ras GTPase-activating proteins protein, RASAL3, which is predominantly expressed in cells of hematopoietic lineages, including NKT, B, and T cells. We established systemic RASAL3-deficient mice, and the mice exhibited a severe decrease in NKT cells in the liver at 8 weeks of age. The treatment of RASAL3-deficient mice with α-GalCer, a specific agonist for NKT cells, induced liver damage, but the level was less severe than that in RASAL3-competent mice, and the attenuated liver damage was accompanied by a reduced production of interleukin-4 and interferon-γ from NKT cells. RASAL3-deficient NKT cells treated with α-GalCer in vitro presented augmented Erk phosphorylation, suggesting that there is dysregulated Ras signaling in the NKT cells of RASAL3-deficient mice. Taken together, these results suggest that RASAL3 plays an important role in the expansion and functions of NKT cells in the liver by negatively regulating Ras/Erk signaling, and might be a therapeutic target for NKT-associated diseases.
authors: Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors: Suguru
authors: S
authors: Saito
authors: Division of Immunology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors: Toshihiko
authors: T
authors: Kawamura
authors: Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors: Masaya
authors: M
authors: Higuchi
authors: Division of Immunology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors: Takahiro
authors: T
authors: Kobayashi
authors: Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.|Center for Fostering Innovative Leadership, Niigata University, Niigata, Japan.
authors: Manami
authors: M
authors: Yoshita-Takahashi
authors: Division of Neurocellular Biology, Brain Research Center, Niigata University, Niigata, Japan.
authors: Maya
authors: M
authors: Yamazaki
authors: Division of Neurocellular Biology, Brain Research Center, Niigata University, Niigata, Japan.
authors: Manabu
authors: M
authors: Abe
authors: Division of Neurocellular Biology, Brain Research Center, Niigata University, Niigata, Japan.
authors: Kenji
authors: K
authors: Sakimura
authors: Division of Immunology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors: Yasuhiro
authors: Y
authors: Kanda
authors: Department of Clinical Engineering and Medical Technology, Faculty of Medical Technology, Niigata University of Health and Welfare, Niigata, Japan.
authors: Hiroki
authors: H
authors: Kawamura
authors: Division of Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.|Niigata College of Medical Technology, Niigata, Japan.
authors: Shuying
authors: S
authors: Jiang
authors: Division of Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors: Makoto
authors: M
authors: Naito
authors: Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors: Takumi
authors: T
authors: Yoshizaki
authors: Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors: Masahiko
authors: M
authors: Takahashi
authors: Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors: Masahiro
authors: M
authors: Fujii
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D005699:Galactosylceramides / Q000008:administration & dosage / Q000276:immunology; D055785:Gene Knockdown Techniques; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D019169:Jurkat Cells; D008099:Liver / Q000276:immunology / Q000293:injuries / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054387:Receptors, CXCR / Q000378:metabolism; D000075744:Receptors, CXCR6; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: C482906:Cxcr6 protein, mouse; D005699:Galactosylceramides; D016169:Lymphocyte Function-Associated Antigen-1; C000599900:RASAL3 protein, human; C000599901:RASAL3 protein, mouse; D012333:RNA, Messenger; D054387:Receptors, CXCR; D000075744:Receptors, CXCR6; C493154:alpha-galactosylceramide; D020703:ras GTPase-Activating Proteins; D015847:Interleukin-4; D007371:Interferon-gamma
keywords: IL-4; Liver injury; NKT cell; Ras; RasGAP; α-GalCer