The human T-cell leukemia virus type 1 oncoprotein tax controls forkhead box O4 activity through degradation by the
Alexandra Oteiza1, Nadir Mechti
1CNRS UMR 5236, Centre d'Études d'Agents Pathogènes et Biotechnologie pour la Santé (CPBS), 1919 Route de Mende, 34 293 Montpellier Cedex 5, France.
Abstract:
Activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway by the viral Tax oncoprotein plays a pivotal role in clonal expansion of human T-cell leukemia virus type 1 (HTLV-1)-infected cells. As the Forkhead box O (FoxO) tumor suppressors act as downstream effectors of PI3K/Akt, they represent good candidate targets whose dysregulation by Tax might be involved in HTLV-1-mediated activation and transformation of infected cells. In this report, we provide evidence showing that Tax induces a dose-dependent degradation of FoxO4 by the ubiquitin-proteasome pathway. Consistent with that, we demonstrate that Tax expression increases the interaction between FoxO4 and Mdm2 E3 ligase, leading to a strong FoxO4 polyubiquitination. These processes require the phosphorylation of FoxO4 by Akt, since a mutant of FoxO4 with mutations on its three Akt phosphorylation sites appears to be resistant to Tax-mediated degradation and ubiquitination. In addition, we show that Tax expression is associated with degradation and phosphorylation of endogenous FoxO4 in Jurkat T cells. Finally, we demonstrate that Tax represses FoxO4 transcriptional activity. Our study demonstrates that Tax can control FoxO4 protein stability and transcriptional activity and provides new insight into the subversion of cell signaling pathways during HTLV-1 infection.
Insights
The viral Tax protein from human T-cell leukemia virus type 1 (HTLV-1) degrades the FoxO4 tumor suppressor via the ubiquitin-proteasome pathway, promoting infected cell activation and transformation.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway is crucial for human T-cell leukemia virus type 1 (HTLV-1) infected cell proliferation.
- Forkhead box O (FoxO) proteins are tumor suppressors regulated by the PI3K/Akt pathway.
Purpose of the Study:
- To investigate the role of the viral Tax oncoprotein in the dysregulation of FoxO tumor suppressors in HTLV-1 infection.
- To elucidate the mechanisms by which Tax affects FoxO4 stability and activity.
Main Methods:
- Western blotting to assess protein degradation and ubiquitination.
- Co-immunoprecipitation to study protein interactions.
- Site-directed mutagenesis to analyze phosphorylation sites.
- Reporter assays to measure transcriptional activity.
Main Results:
- Tax induces dose-dependent degradation of FoxO4 via the ubiquitin-proteasome pathway.
- Tax enhances the interaction between FoxO4 and Mdm2 E3 ligase, promoting FoxO4 polyubiquitination.
- Akt-mediated phosphorylation of FoxO4 is essential for Tax-induced degradation and ubiquitination.
- Tax represses FoxO4 transcriptional activity and leads to degradation of endogenous FoxO4 in Jurkat T cells.
Conclusions:
- Tax controls FoxO4 protein stability and transcriptional activity.
- This study provides insights into how Tax subverts cellular signaling pathways during HTLV-1 infection, contributing to oncogenesis.
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