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Infectious medicine, virology

A20 targets caspase-8 and FADD to protect HTLV-I-infected cells

Leukemia volume 30, pages 716–727 (2016)Cite this article

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Abstract

Adult T-cell leukemia (ATL) arises from a human T-cell leukemia virus type I (HTLV-I)-infected cell and has few therapeutic options. Here, we have uncovered a previously unrecognized role for a ubiquitin-editing enzyme A20 in the survival of HTLV-I-infected cells. Unlike in lymphomas of the B-cell lineage, A20 is abundantly expressed in primary ATL cells without notable mutations. Depletion of A20 in HTLV-I-infected cells resulted in caspase activation, cell death induction and impaired tumorigenicity in mouse xenograft models. Mechanistically, A20 stably interacts with caspase-8 and Fas-associated via death domain (FADD) in HTLV-I-infected cells. Mutational studies revealed that A20 supports the growth of HTLV-I-infected cells independent of its catalytic functions and that the zinc-finger domains are required for the interaction with and regulation of caspases. These results indicate a pivotal role for A20 in the survival of HTLV-I-infected cells and implicate A20 as a potential therapeutic target in ATL.

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Acknowledgements

The authors thank the following researchers for providing invaluable materials: Dr D Wallach for pcDNA3-HA-A20, Dr ISY Chen for pHCMV-VSV-G and pCMVΔR8.2 packaging plasmids, Dr H Miyoshi (RIKEN, Japan) for the CS-CDF-CG-PRE plasmid, Dr M Higuchi and Dr M Fujii for CSII-EF-IB-RfA and CSII-EF-IB, and Dr S Uota (T.M.D.U., Tokyo, Japan) for CS-κB-R2.2 and pCERp plasmids. This work was supported in part by a grant-in-aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan to SY (22117004) and YS (26860207) and in part by a grant-in-aid for Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development to SY (015).

Author contributions

YS and SY designed research and SY supervised the work. YS, KM, AH, AK and HI performed biochemical experiments, MU provided support with the animal experiments, YS, KM, ET and FT contributed to lentiviral vector constructions, and AU and TW collected and analyzed blood samples from ATL patients. YS and SY wrote the manuscript and all the authors checked the final version of the manuscript.

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  1. A Hamano and K Mochida: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    Y Saitoh, A Hamano, K Mochida, A Kakeya, M Uno, E Tsuruyama, H Ichikawa & S Yamaoka

  2. Department of Comprehensive Reproductive Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    M Uno

  3. Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan

    F Tokunaga

  4. Department of Hematology, Imamura Bun-in Hospital, Kagoshima, Japan

    A Utsunomiya

  5. Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan

    T Watanabe

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  1. Y Saitoh
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Correspondence to S Yamaoka.

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Saitoh, Y., Hamano, A., Mochida, K. et al. A20 targets caspase-8 and FADD to protect HTLV-I-infected cells. Leukemia 30, 716–727 (2016). https://doi.org/10.1038/leu.2015.267

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