HTLV-1 tax is a critical lipid raft modulator that hijacks IκB kinases to the microdomains for persistent activation of NF-κB

Abstract

Upon T cell activation, IκB kinases (IKKs) are transiently recruited to the plasma membrane-associated lipid raft microdomains for activation of NF-κB 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-κB 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 IκB 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 IKKγ, and accordingly, depletion of IKKγ impairs Tax1-directed lipid raft recruitment of IKKα and IKKβ. In contrast, Tax2 activates NF-κB 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-κB, thereby contributing to HTLV-1 oncogenesis. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.