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The tyrosine kinase KDR is essential for the survival of HTLV-1-infected T cells by stabilizing the Tax oncoprotein

Author

Listed:
  • Suchitra Mohanty

    (Penn State College School of Medicine)

  • Sujit Suklabaidya

    (Penn State College School of Medicine)

  • Alfonso Lavorgna

    (Johns Hopkins School of Medicine
    Millipore-Sigma)

  • Takaharu Ueno

    (Kansai Medical University)

  • Jun-ichi Fujisawa

    (Kansai Medical University)

  • Nyater Ngouth

    (National Institutes of Health)

  • Steven Jacobson

    (National Institutes of Health)

  • Edward W. Harhaj

    (Penn State College School of Medicine)

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) infection is linked to the development of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax oncoprotein regulates viral gene expression and persistently activates NF-κB to maintain the viability of HTLV-1-infected T cells. Here, we utilize a kinome-wide shRNA screen to identify the tyrosine kinase KDR as an essential survival factor of HTLV-1-transformed cells. Inhibition of KDR specifically induces apoptosis of Tax expressing HTLV-1-transformed cell lines and CD4 + T cells from HAM/TSP patients. Furthermore, inhibition of KDR triggers the autophagic degradation of Tax resulting in impaired NF-κB activation and diminished viral transmission in co-culture assays. Tax induces the expression of KDR, forms a complex with KDR, and is phosphorylated by KDR. These findings suggest that Tax stability is dependent on KDR activity which could be exploited as a strategy to target Tax in HTLV-1-associated diseases.

Suggested Citation

  • Suchitra Mohanty & Sujit Suklabaidya & Alfonso Lavorgna & Takaharu Ueno & Jun-ichi Fujisawa & Nyater Ngouth & Steven Jacobson & Edward W. Harhaj, 2024. "The tyrosine kinase KDR is essential for the survival of HTLV-1-infected T cells by stabilizing the Tax oncoprotein," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49737-5
    DOI: 10.1038/s41467-024-49737-5
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    1. Huanjiao Jenny Zhou & Zhe Xu & Zongren Wang & Haifeng Zhang & Zhen W. Zhuang & Michael Simons & Wang Min, 2018. "SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
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