HIV-1 Tat impairs cell cycle control by targeting the Tip60, Plk1 and cyclin B1 ternary complex

• Published in: Cell cycle (Georgetown, Tex.) Tex.), 2012-03, Vol.11 (6), p.1217-1234
• Main Authors: Zhang, Shi-Meng, Song, Maoyong, Yang, Tian-Yi, Fan, Rong, Liu, Xiao-Dan, Zhou, Ping-Kun
• Format: Article
• Language: English
• Subjects: Acetylation; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cell Cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Nucleus - genetics; Cell Nucleus - metabolism; Centrosome - metabolism; Cycle; Cyclin B1; Cyclin B1 - genetics; Cyclin B1 - metabolism; Fluorescent Antibody Technique; Genetic Vectors - genetics; Genetic Vectors - metabolism; HEK293 Cells; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; HIV; HIV-1 - metabolism; Humans; Landes; Lysine Acetyltransferase 5; Organogenesis; phosphorylation; Plk1; Polo-Like Kinase 1; Protein Binding; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein Transport; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Tat; tat Gene Products, Human Immunodeficiency Virus - metabolism; Ternary Complex Factors - genetics; Ternary Complex Factors - metabolism; Time-Lapse Imaging; Tip60; Transfection
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.11.6.19664

HIV-1 Tat triggers intrinsic and extrinsic apoptosis pathways in both infected and uninfected cells and plays an important role in the pathogenesis of AIDS. Knocking down Tip60, an interactive protein of Tat, leads to the impairment of cell cycle progression, indicating a key role of Tip60 in cell cycle control. We found that Tip60 interacts with Plk1 through its ZnFMYST domain, and that this interaction is enhanced in the G 2 /M phase. In addition, cyclin B1 was confirmed to interact with the ZnF domain of Tip60. Immunofluorescence imaging showed that Tip60 co-localizes with both Plk1 and cyclin B1 at the centrosome during the mitotic phase and to the mid-body during cytokinesis. Further experiments revealed that Tip60 forms a ternary complex with Plk1 and cyclin B1 and acetylates Plk1 but not cyclin B1. HIV-1 Tat likely forms a quaternary complex with Tip60, cyclin B1 and Plk1. Fluorescent microscopy showed that Tat causes an unscheduled nuclear translocation of both cyclin B1 and Plk1, causing their co-localization with Tip60 in the nucleus. Tat, Tip60, cyclin B1 and Plk1 interactions provide new a mechanistic explanation for Tat-mediated cell cycle dysregulation and apoptosis.