1. The tyrosine kinase KDR is essential for the survival of HTLV-1-infected T cells by stabilizing the Tax oncoprotein.
- Author
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Mohanty, Suchitra, Suklabaidya, Sujit, Lavorgna, Alfonso, Ueno, Takaharu, Fujisawa, Jun-ichi, Ngouth, Nyater, Jacobson, Steven, and Harhaj, Edward W.
- Subjects
T cells ,PROTEIN-tyrosine kinases ,HTLV-I ,ADULT T-cell leukemia ,CELL transformation ,BOVINE viral diarrhea - 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. The human T-cell leukemia virus type 1 Tax oncoprotein plays essential roles in regulating viral gene expression and cell survival. Here, the authors show that Tax requires the tyrosine kinase KDR to prevent its degradation by autophagy. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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