Activation of human T cell leukemia virus type 1 (HTLV-1) transcription is established through the formation of protein complexes on the viral promoter that are essentially composed of the cellular basic leucine zipper (bZIP) transcription factor cAMP-response element-binding protein (CREB (or certain other members of the ATF/CREB family), the HTLV-1-encoded transactivator Tax, and the pleiotropic cellular coactivators p300/CBP. HTLV-1 bZIP factor (HBZ) is a protein encoded by HTLV-1 that contains a bZIP domain and functions to repress HTLV-1 transcription. HBZ has been shown to repress viral transcription by dimerizing with CREB, which occurs specifically through the bZIP domain in each protein, and preventing CREB from binding to the DNA. However, we previously found that HBZ causes only partial removal of CREB from a chromosomally integrated viral promoter, and more importantly, an HBZ mutant lacking the COOH-terminal bZIP domain retains the ability to repress viral transcription. These results suggest that an additional mechanism contributes to HBZ-mediated repression of HTLV-1 transcription. In this study, we show that HBZ binds directly to the p300 and CBP coactivators. Two LXXLL-like motifs located within the NH 2 -terminal region of HBZ are important for this interaction and specifically mediate binding to the KIX domain of p300/CBP. We provide evidence that this interaction interferes with the ability of Tax to bind p300/CBP and thereby inhibits the association of the coactivators with the viral promoter. Our findings demonstrate that HBZ utilizes a bipartite mechanism to repress viral transcription.Human T-cell leukemia virus type 1 (HTLV-1) 5 is a retrovirus that is the causative agent of adult T-cell leukemia and a neurodegenerative disorder termed tropical spastic paraparesis/HTLV-1-associated myelopathy (1, 2). Following its integration, the provirus utilizes the cellular RNA polymerase II transcription machinery for replication of the viral genome and expression of viral genes. These processes are dependent on the viral transactivator Tax, which is essential for strong activation of HTLV-1 transcription. Tax alone lacks DNA binding activity and is therefore recruited to the viral promoter as part of a complex with the cellular transcription factor CREB or other members of the activating transcription factor/cyclic AMP-responsive element (CRE)-binding protein (ATF/CREB) family (3-6). These proteins carry a basic leucine zipper (bZIP) domain that stimulates protein dimerization and subsequent DNA binding. Dimer formation is specifically mediated through the leucine zipper (ZIP) domain, whereas DNA binding involves the basic region of each binding partner directly contacting the DNA. The Tax-CREB complexes associate with three Tax-responsive elements called viral CREs (vCREs) within the viral promoter that encompasses the U3 region of the 5Ј-long terminal repeat of the provirus. Each vCRE contains a central sequence similar to that of a cellular CRE that is recognized by CREB and flanking GC-rich s...

Human T-cell leukemia virus types 3 and 4 (HTLV-3 05296-11). Here, we demonstrate that Jun transcription factors are differently affected by APH-3 and APH-4 compared to HBZ. These intriguing findings suggest that these proteins act differently on viral replication but also on cellular gene expression, and that highlighting their differences of action might lead to important information allowing us to understand the link between HTLV-1 HBZ and ATL in infected individuals.

Amphiphysin 2 (BIN1) is a membrane and actin remodeling protein mutated both in congenital and adult centronuclear myopathies. The BIN1 muscle-specific isoform finely tunes muscle regeneration in adulthood and regulates myoblast fusion. However, the underlying molecular mechanisms are unknown. Here, we report that BIN1 is required for myoblast fusion and participates in the formation of filopodia-like structures at myoblasts intercellular junctions. BIN1 bundles actin in vitro and regulates the membrane-to-cortex attachment, two key processes required for myoblast fusion. We identified ezrin as a new BIN1 partner and showed that BIN1 promotes ezrin association to PI(4,5)P2 at the membrane cortex. Our results establish BIN1 and ezrin as key players at the early stages of myoblast fusion for the formation of long-lived filopodia-like structures.

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Clathrin-mediated endocytosis is a paradigm of a cellular processes that is orchestrated by phosphoinositides, where the plasma membrane phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) plays an instrumental role in the formation of clathrin-coated structures. Among the early endocytic proteins that reach at the plasma membrane, the F-BAR domain only protein 1 and 2 complex (FCHo1/2) is thought to orchestrate the early stages but, the exact mechanism triggering its nucleation on membranes is not well understood. By combining bottom-up synthetic approaches on in vitro and cellular membranes, we show the molecular dynamics of FCHo2 self-assembly on membranes. Our results indicate that PI(4,5)P2 guide the recruitment of FCHo2 at specific regions of the membrane, where it self-assembles into ring-like shape protein patches flanked by membrane invaginations. Importantly, we show that binding of FCHo2 on cellular membranes promotes the enrichment of PI(4,5)P2 at the boundary of specific cargo receptors, such as the epidermal growth factor receptor (EGFR). Thus, our results provide a mechanistic framework that could explain the orchestration of early PI(4,5)P2-interacting proteins recruitment at endocytic sites.