HTLV-1 Tax deregulates autophagy by recruiting autophagic molecules into lipid raft microdomains

• Published in: Oncogene Vol. 34; no. 3; pp. 334 - 345
• Main Authors: Ren, T, Takahashi, Y, Liu, X, Loughran, T P, Sun, S-C, Wang, H-G, Cheng, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.01.2015; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/67/1990/291/1621/1916; 631/80/82/39; 631/80/86; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Autophagy; Autophagy (Cytology); Beclin-1; Carcinogenesis; CD4 antigen; Cell activation; Cell Biology; Cell Line, Tumor; Cells, Cultured; Cellular signal transduction; Enzyme inhibitors; Gene Products, tax - genetics; Gene Products, tax - metabolism; Genetic aspects; Genetic regulation; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Health aspects; Host-Pathogen Interactions; Human Genetics; Human T-lymphotropic virus 1; Human T-lymphotropic virus 1 - genetics; Human T-lymphotropic virus 1 - metabolism; Human T-lymphotropic virus 1 - physiology; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; IKK protein; Immunoblotting; Immunological memory; Internal Medicine; Jurkat Cells; Leukemia; Lipid rafts; Lipids; Lymphocyte transformation; Lymphocytes; Lymphocytes T; Lymphoma; Medicine; Medicine & Public Health; Membrane Microdomains - metabolism; Membrane Microdomains - virology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Memory cells; Microscopy, Fluorescence; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mutation; Oncogenes; Oncology; original-article; Phagocytosis; Phagosomes; Phagosomes - metabolism; Phagosomes - virology; Phosphatidylinositol 3-Kinases; Protein expression; Risk factors; Signal transduction; T cells; T-Lymphocytes - metabolism; T-Lymphocytes - virology; Tax protein; Tumor proteins; United States; Bif-1; IKK; lipid rafts; Beclin1; autophagy; HTLV-1 Tax
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.552

The retroviral oncoprotein Tax from human T-cell leukemia virus type 1 (HTLV-1), an etiological factor that causes adult T-cell leukemia and lymphoma, has a crucial role in initiating T-lymphocyte transformation by inducing oncogenic signaling activation. We here report that Tax is a determining factor for dysregulation of autophagy in HTLV-1-transformed T cells and Tax-immortalized CD4 memory T cells. Tax facilitated autophagic process by activating inhibitor of κB (IκB) kinase (IKK) complex, which subsequently recruited an autophagy molecular complex containing Beclin1 and Bif-1 to the lipid raft microdomains. Tax engaged a crosstalk between IKK complex and autophagic molecule complex by directly interacting with both complexes, promoting assembly of LC3+ autophagosomes. Moreover, expression of lipid raft-targeted Bif-1 or Beclin1 was sufficient to induce formation of LC3+ autophagosomes, suggesting that Tax recruitment of autophagic molecules to lipid rafts is a dominant strategy to deregulate autophagy in the context of HTLV-1 transformation of T cells. Furthermore, depletion of autophagy molecules such as Beclin1 and PI3 kinase class III resulted in impaired growth of HTLV-1-transformed T cells, indicating a critical role of Tax-deregulated autophagy in promoting survival and transformation of virally infected T cells.