HTLV-1 Tax is a critical lipid raft modulator that hijacks IkappaB kinases to the microdomains for persistent activation of NF-kappaB.
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.
Huang
Jiannan
J
Penn State Cancer Institute, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Ren
Tong
T
Guan
Hui
H
Jiang
Yixing
Y
Cheng
Hua
H
D049109:Cell Proliferation; D002472:Cell Transformation, Viral / Q000502:physiology*; D004789:Enzyme Activation; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D015490:HTLV-I Infections / Q000235:genetics / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
D016356:Gene Products, tax; D016328:NF-kappa B; D051550:I-kappa B Kinase