Human T-lymphotropic Virus, Type 1, Tax Protein Triggers Microtubule Reorientation in the Virological Synapse

Abstract

We showed recently that the human T-lymphotropic virus, type 1 (HTLV-1), spreads directly from cell to cell via a virological synapse. The HTLV-1 virological synapse resembles the immunological synapse; each is a specialized contact between a lymphocyte and another cell that contains organized protein microdomains, and each involves repolarization of the T-cell microtubule cytoskeleton. However, formation of the virological synapse is not triggered by T-cell receptor-mediated antigen recognition. On the basis of our previous data, we postulated that formation of the viral synapse was triggered by a conjunction of two signals, one from HTLV-1 infection of the T-cell and one from cell-cell contact. We have recently identified ICAM-1 engagement as a cellcontact signal that causes the microtubule polarization associated with the virological synapse. Here we used confocal microscopy of T-lymphocytes naturally infected with HTLV-1 or transfected with individual HTLV-1 genes to investigate the role of the viral transcriptional transactivator protein Tax. Polarization of the microtubules was induced by cell-cell contact or by cross-linking T-cell surface molecules with monoclonal antibodies adsorbed to latex beads. We show that Tax, which is mainly found in the nucleus, is also present at two specific extranuclear sites as follows: around the microtubule organizing center in association with the cis-Golgi and in the cell-cell contact region. We show that expression of Tax provides an intracellular signal that synergizes with ICAM-1 engagement to cause the T-cell microtubule polarization observed at the virological synapse.

Activation of NF-κB by the Human T Cell Leukemia Virus Type I Tax Oncoprotein Is Associated with Ubiquitin-dependent Relocalization of IκB Kinase

“…Our findings are supported by several previous reports indicating that a substantial fraction of Tax colocalizes with the Golgi apparatus (17,29,34). Tax appears to be localized partially in the cis-Golgi adjacent to the microtubule organizing center in naturally infected T lymphocytes from HTLV-1-associated myelopathy/tropical spastic paraparesis patients (29).…”

“…Thus, it appears that IKK is localized within or is associated with the Golgi apparatus in HTLV-1 transformed cells. In support of these observations, a recent study has demonstrated that Tax is localized, at least partially, in the cis-Golgi stacks in transfected cells as well as naturally infected T lymphocytes from HTLV-1-associated myelopathy/tropical spastic paraparesis patients (29). Because the Golgi apparatus is a major site of signal transduction (30), the Tax-mediated IKK relocalization to this site may be an important mechanism of IKK activation.…”

Ubiquitylated Tax targets and binds the IKK signalosome at the centrosome

“…Tax colocalizes with the centrosome and triggers microtubule reorientation (Nejmeddine et al, 2005). CREB activation is required for MTOC/Tax orientation to the cell-cell contact region, but not for Tax/MTOC association (Nejmeddine et al, 2005).…”

“…Tax colocalizes with the centrosome and triggers microtubule reorientation (Nejmeddine et al, 2005). CREB activation is required for MTOC/Tax orientation to the cell-cell contact region, but not for Tax/MTOC association (Nejmeddine et al, 2005). That the Tax mutant M47 recruited IKK to the centrosome demonstrates that Tax-induced CREB Harhaj et al (2007), recently reported an association between perinuclear IKK and Tax that colocalize to the Golgi, we documented using complementary approaches that Tax/IKK complexes are associated with the centrosome rather than the Golgi apparatus.…”

“…In the nucleus, Tax is predominantly located in RelA-enriched nuclear bodies (Bex et al, 1998). In the cytoplasm, a substantial fraction of Tax lays in perinuclear speckles, adjacent to the centrosome or microtubule organizing center (MTOC), in close association with the cis-Golgi compartment (Nejmeddine et al, 2005). Tax targets the centrosomal protein Tax1BP2, causing centrosome amplification, genomic instability and aneuploidy (Ching et al, 2006;Nitta et al, 2006;Pumfery et al, 2006).…”