Format

Send to

Choose Destination
Eur J Immunol. 2015 May;45(5):1512-23. doi: 10.1002/eji.201444977. Epub 2015 Mar 11.

RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells.

Author information

1
Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
2
Division of Immunology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
3
Center for Fostering Innovative Leadership, Niigata University, Niigata, Japan.
4
Division of Neurocellular Biology, Brain Research Center, Niigata University, Niigata, Japan.
5
Department of Clinical Engineering and Medical Technology, Faculty of Medical Technology, Niigata University of Health and Welfare, Niigata, Japan.
6
Division of Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
7
Niigata College of Medical Technology, Niigata, Japan.

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.

KEYWORDS:

IL-4; Liver injury; NKT cell; Ras; RasGAP; α-GalCer

PMID:
25652366
DOI:
10.1002/eji.201444977
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center