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HTLV-1 HBZ positively regulates the mTOR signaling pathway via inhibition of GADD34 activity in the cytoplasm

Oncogene volume 33, pages 2317–2328 (2014)Cite this article

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Abstract

Human T-cell leukemia virus type-1 (HTLV-1) infection causes adult T-cell leukemia (ATL). Modulation of the transcriptional control of cellular genes by HTLV-1 is thought to be associated with the development of ATL. The viral protein HTLV-1 basic leucine-zipper factor (HBZ) has been shown to dysregulate the activity of cellular transcription factors. Here, we demonstrate that HBZ is exported from the nucleus to the cytoplasm, where it activates the mammalian target of rapamycin (mTOR) signaling pathway through an association with growth arrest and DNA damage gene 34 (GADD34). The N-terminal region of HBZ interacts with the C-terminal region of GADD34. HBZ contains a functional nuclear export signal (NES) sequence within its N-terminal region and it is exported from the nucleus via the CRM1-dependent pathway. Nuclear export of HBZ is essential for its interaction with GADD34 and increased phosphorylation of S6 kinase, which is an established downstream target of the mTOR pathway. Starvation-induced autophagy is significantly suppressed by the overexpression of HBZ. These findings indicate that HBZ is actively exported to the cytoplasm, where it dysregulates the function of cellular factors.

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Acknowledgements

We thank Dr H. Miyoshi for providing the lentivirus-based transfection system. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas ‘Integrative Research Toward the Conquest of Cancer’ from the Ministry of Education, Culture, Sports, Science and Technology of Japan. In addition, this work was supported, in part, by research funds from the Takeda Science Foundation, the Suzuken Memorial Foundation and the Japanese Leukemia Research Foundation. R. Mukai was supported by a Research Fellowship from JSPS for Young Scientists.

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  1. Faculty of Engineering, Tokushima Bunri University, Sanuki, Kagawa, Japan

    R Mukai & T Ohshima

  2. Faculty of Pharmaceutical Science at Kagawa Campus, Tokushima Bunri University, Sanuki, Kagawa, Japan

    T Ohshima

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Correspondence to T Ohshima.

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Mukai, R., Ohshima, T. HTLV-1 HBZ positively regulates the mTOR signaling pathway via inhibition of GADD34 activity in the cytoplasm. Oncogene 33, 2317–2328 (2014). https://doi.org/10.1038/onc.2013.181

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