Human T-cell leukemia virus type 1 Tax induces an aberrant clustering of the tumor suppressor Scribble through the PDZ domain-binding motif dependent and independent interaction.

摘要

Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of adult T-cell leukemia. HTLV-1 Tax1 transforming protein interacts with several PDZ domain-containing proteins, and the interaction is associated with the transforming activities of Tax1 as well as persistent HTLV-1 infection. In this study, we show that Tax1 interacts with the tumor suppressor Scribble containing PDZ domains. Unlike other Tax1-interacting PDZ domain proteins, the PDZ domain-binding motif (PBM) of Tax1 was not required for the interaction with transiently expressed Scribble in 293T cells, but it was essential for the interaction with endogenous Scribble. Endogenous Scribble in 293T cells was primarily localized at the plasma membrane and colocalized with Tax1 but not Tax1C lacking PBM, whereas transiently expressed Scribble was localized in the cytoplasm and colocalized with Tax1C as well as Tax1, thus suggesting that Tax1 is recruited to the site of endogenous Scribble, such as the plasma membrane, in a PBM-dependent manner, and thereafter it interacts with Scribble in a PBM-independent and PBM-dependent manner. Endogenous Scribble was diffusely localized at the plasma membrane of HTLV-1-uninfected T-cell lines, whereas it colocalized with Tax1 as small and large aggregate at the plasma membranes. These results suggest that Tax1 through two binding sites induce aberrant clustering of Scribble, thereby altering the functions in HTLV-1-infected cells, which may thus play a role in persistent HTLV-1 infection and the pathogenesis.