Huang Jiannan, Ren Tong, Guan Hui, Jiang Yixing, Cheng Hua
Penn State Cancer Institute, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA.
J Biol Chem. 2009 Mar 6;284(10):6208-17. doi: 10.1074/jbc.M806390200. Epub 2009 Jan 7.
Upon T cell activation, IkappaB kinases (IKKs) are transiently recruited to the plasma membrane-associated lipid raft microdomains for activation of NF-kappaB in promoting T cell proliferation. Retroviral Tax proteins from human T cell leukemia virus type 1 and type 2 (HTLV-1 and -2) are capable of activating IKK, yet only HTLV-1 infection causes T cell leukemia, which correlates with persistent activation of NF-kappaB induced by Tax1. Here, we show that the Tax proteins exhibit differential modes of IKK activation. The subunits of IKK are constitutively present in lipid rafts in activated forms in HTLV-1-infected T cells that express Tax. Disruption of lipid rafts impairs IkappaB kinase activation by Tax1. We also show that the cytoplasmic Tax1 protein persistently resides in the Golgi-associated lipid raft microdomains. Tax1 directs lipid raft translocation of IKK through selective interaction with IKKgamma and accordingly, depletion of IKKgamma impairs Tax1-directed lipid raft recruitment of IKKalpha and IKKbeta. In contrast, Tax2 activates NF-kappaB in a manner independent of lipid raft recruitment of IKK. These findings indicate that Tax1 actively recruits IKK to the lipid raft microdomains for persistent activation of NF-kappaB, thereby contributing to HTLV-1 oncogenesis.
T细胞激活后，IκB激酶（IKKs）会短暂募集到与质膜相关的脂筏微结构域，以激活NF-κB从而促进T细胞增殖。来自1型和2型人类T细胞白血病病毒（HTLV-1和-2）的逆转录病毒Tax蛋白能够激活IKK，但只有HTLV-1感染会导致T细胞白血病，这与Tax1诱导的NF-κB持续激活相关。在此，我们表明Tax蛋白表现出不同的IKK激活模式。在表达Tax的HTLV-1感染的T细胞中，IKK的亚基以激活形式组成性地存在于脂筏中。脂筏的破坏会损害Tax1对IκB激酶的激活。我们还表明，细胞质中的Tax1蛋白持续存在于与高尔基体相关的脂筏微结构域中。Tax1通过与IKKγ的选择性相互作用引导IKK向脂筏转位，因此，IKKγ的缺失会损害Tax1引导的IKKα和IKKβ向脂筏的募集。相比之下，Tax2以独立于IKK向脂筏募集的方式激活NF-κB。这些发现表明，Tax1积极地将IKK募集到脂筏微结构域以持续激活NF-κB，从而促进HTLV-1的肿瘤发生。
