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

Suchitra Mohanty, Sujit Suklabaidya, Alfonso Lavorgna, Takaharu Ueno, Jun-ichi Fujisawa, Nyater Ngouth, Steven Jacobson and Edward W. Harhaj ()
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Suchitra Mohanty: Penn State College School of Medicine
Sujit Suklabaidya: Penn State College School of Medicine
Alfonso Lavorgna: Johns Hopkins School of Medicine
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

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49737-5

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