Guo Rishu, Wan Chi-Keung, Carpenter Jeffery H, Mousallem Talal, Boustany Rose-Mary N, Kuan Chien-Tsun, Burks A Wesley, Zhong Xiao-Ping
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11909-14. doi: 10.1073/pnas.0711856105. Epub 2008 Aug 8.
Diacylglycerol (DAG) kinases (DGKs) are a family of enzymes that convert DAG to phosphatidic acid (PA), the physiologic functions of which have been poorly defined. We report here that DGK alpha and zeta synergistically promote T cell maturation in the thymus. Absence of both DGKalpha and zeta (DGKalpha(-/-)zeta(-/-)) results in a severe decrease in the number of CD4(+)CD8(-) and CD4(-)CD8(+) single-positive thymocytes correlating with increased DAG-mediated signaling. Positive selection, but not negative selection, is impaired in DGKalpha(-/-)zeta(-/-) mice. The developmental blockage in DGKalpha(-/-)zeta(-/-) mice can be partially overcome by treatment with PA. Furthermore, decreased DGK activity also promotes thymic lymphomagenesis accompanying elevated Ras and Erk1/2 activation. Our data demonstrate a synergistic and critical role of DGK isoforms in T cell development and tumor suppression, and indicate that DGKs not only terminate DAG signaling but also initiate PA signaling in thymocytes to promote positive selection.
二酰基甘油激酶（DGK）是一类将二酰基甘油（DAG）转化为磷脂酸（PA）的酶，其生理功能一直未得到很好的界定。我们在此报告，DGKα和ζ协同促进胸腺中T细胞的成熟。DGKα和ζ均缺失（DGKα（-/-）ζ（-/-））会导致CD4（+）CD8（-）和CD4（-）CD8（+）单阳性胸腺细胞数量严重减少，这与DAG介导的信号传导增加相关。在DGKα（-/-）ζ（-/-）小鼠中，阳性选择而非阴性选择受到损害。用PA处理可部分克服DGKα（-/-）ζ（-/-）小鼠的发育阻滞。此外，DGK活性降低还会伴随着Ras和Erk1/2激活升高促进胸腺淋巴瘤的发生。我们的数据证明了DGK同工型在T细胞发育和肿瘤抑制中的协同关键作用，并表明DGK不仅终止DAG信号传导，还在胸腺细胞中启动PA信号传导以促进阳性选择。
