Interference of HTLV-1 Tax Protein with Cell Polarity Regulators: Defining the Subcellular Localization of the Tax-DLG1 Interaction

Abstract

Human T cell leukemia virus (HTLV)-1 Tax (Tax) protein is very important in viral replication and cell transformation. Tax localizes in the nucleus and cytoplasm in association with organelles. Some activities of Tax depend on interactions with PDZ (PSD-95/Discs Large/Z0-1) domain–containing proteins such as Discs large protein 1 (DLG1) which is involved in cell polarity and proliferation. The DLG1 interaction results in a cytoplasmic co-localization pattern resembling vesicular aggregates, the nature of which is still unknown. To further explore the role of PDZ proteins in HTLV-1 cell transformation, we deeply investigated the Tax-DLG1 association. By fluorescence resonance energy transfer (FRET), we detected, for the first time, the direct binding of Tax to DLG1 within the cell. We showed that the interaction specifically affects the cellular distribution of not only DLG1, but also Tax. After studying different cell structures, we demonstrated that the aggregates distribute into the Golgi apparatus in spatial association with the microtubule-organizing center (MTOC). This study contributes to understand the biological significance of Tax-PDZ interactions.

Novel effect of the high risk-HPV E7 CKII phospho-acceptor site on polarity protein expression

“…The DNA sequence coding for hScrib was cloned into HA-tagged pCDNA-3 plasmid, resulting in pCDNA-HA-Scrib. The pegfp-DLG1 and pmTurq2-DLG1 vectors were previously described [ 14 , 33 ]. A plasmid encoding β-galactoside (β-gal) protein was included in all transfections as a control of equal transfection efficiency.…”

Identification of small molecule antivirals against HTLV-1 by targeting the hDLG1-Tax-1 protein-protein interaction

“…In the context of the full-length proteins, the interaction is believed to proceed via the hDLG1 PDZ1+2 tandem engaging a pair of PBMs in the Tax-1 homodimer, as seen in other complexes of PDZ tandem-bearing proteins with their dimeric partners (Grembecka et al, 2006). While Tax-1-hDLG1 binding was previously biochemically and functionally validated (Aoyagi et al, 2010;Hirata et al, 2004;Marziali et al, 2017;Suzuki et al, 1999), little is known about its molecular determinants, which is essential for structure-based drug discovery.…”

“…In the co-culture assay, inhibition of viral cell-to-cell transmission was tested. One route of HTLV-1 transmission is via virological synapse formation from the Golgi apparatus, which is shown to be promoted by interaction of Tax-1 with PDZs such as those of hDLG1 (Marziali et al, 2017). Consequently, inhibiting this interaction is expected to decrease viral transmission and, therefore, infectivity.…”

Structural insight into the ScribblePDZdomains interaction with the oncogenic Human T‐cell lymphotrophic virus‐1 (HTLV‐1) Tax1PBM

“…Tax1 PBM binds to numerous polarity proteins and leads to the aggregation or mislocalization of Dlg, Scribble, MAGI‐1 and MAGI‐3 [ 33 , 34 , 35 , 36 ], impacting host cell control of cell adhesion, proliferation, and signalling. In humanized CD34+ mice, Tax1 PBM enhances HTLV‐1‐induced T‐cell proliferation [ 33 ].…”