Secretion of the human T cell leukemia virus type I transactivator protein tax.
Human T cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T cell leukemia and HTLV-I-associated myelopathy/tropical spastic paraparesis. The HTLV-I protein Tax is well known as a transcriptional transactivator and inducer of cellular transformation. However, it is also known that extracellular Tax induces the production and release of cytokines, such as tumor necrosis factor-alpha and interleukin-6, which have adverse effects on cells of the central nervous system. The cellular process by which Tax exits the cell into the extracellular environment is currently unknown. In most cell types, Tax has been shown to localize primarily to the nucleus. However, Tax has also been found to accumulate in the cytoplasm. The results contained herein begin to characterize the process of Tax secretion from the cell. Specifically, cytoplasmic Tax was demonstrated to localize to organelles associated with the cellular secretory process including the endoplasmic reticulum and Golgi complex. Additionally, it was demonstrated that full-length Tax was secreted from both baby hamster kidney cells and a human kidney tumor cell line, suggesting that Tax enters the secretory pathway in a leaderless manner. Tax secretion was partially inhibited by brefeldin A, suggesting that Tax migrated from the endoplasmic reticulum to the Golgi complex. In addition, combined treatment of Tax-transfected BHK-21 cells with phorbol myristate acetate and ionomycin resulted in a small increase in the amount of Tax secreted, suggesting that a fraction of cytoplasmic Tax was present in the regulated secretory pathway. These studies begin to provide a link between Tax localization to the cytoplasm, the detection of Tax in the extracellular environment, its possible role as an extracellular effector molecule, and a potential role in neurodegenerative disease associated with HTLV-I infection.
Alefantis
Timothy
T
Department of Microbiology and Immunology, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania 17033, USA.
Mostoller
Kate
K
Jain
Pooja
P
Harhaj
Edward
E
Grant
Christian
C
Wigdahl
Brian
B
D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000378:metabolism; D020126:Brefeldin A / Q000494:pharmacology; D018929:Cell Culture Techniques; D002460:Cell Line; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000196:embryology; D006224:Cricetinae; D003470:Culture Media; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D016356:Gene Products, tax / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D008164:Luminescent Proteins / Q000378:metabolism; D008954:Models, Biological; D009336:Necrosis; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D001426:Bacterial Proteins; D003470:Culture Media; C485182:Cyan Fluorescent Protein; D018076:DNA, Complementary; D016356:Gene Products, tax; D015850:Interleukin-6; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins; D020126:Brefeldin A; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate