Journal of Antivirals & Antiretrovirals
Open Access

Abstract

The HTLV-1 Latency-Maintenance Factor p30II Induces the Phosphorylation and Hypoxia-Independent Mitochondrial Targeting of TIGAR Analogous to Tyrosine Kinase Receptor-Signaling and Suppresses Oncogene-Induced Oxidative Toxicity

Robert Harrod*, Tetiana Bowley, Aditi Malu, Natalie M. Adams, Julia Savage, Melika Saberi, Mya VanderHagen, Reena Alame, Makenna Keating and Courtney Yates

The Human T-Cell Leukemia Virus Type-1 (HTLV-1) is a complex oncoretrovirus that infects CD4+ T-cells and causes an aggressive lympho-neoplastic disease, known as Adult T-Cell Leukemia/Lymphoma (ATLL). Our earlier studies have demonstrated that the HTLV-1 latency-maintenance factor p30II interacts with TIP60, prevents TIP60- mediated K120-acetylation of the TP53 protein, and induces hypoxia-independent mitochondrial targeting of the TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) a 2,6-bisfructose-phosphatase that suppresses the accumulation of damaging Reactive Oxygen Species (ROS) in proliferating cells. Here, we demonstrate that p30II induces serine-phosphorylation of the TIGAR associated with its targeting to mitochondrial membranes in HTLV1-transformed ATLL lymphocytes. Our studies have further revealed that tyrosine kinase growth factor receptorsignaling similarly induces serine-phosphorylation and mitochondrial targeting of the TIGAR correlated with Mycdependent cellular proliferation. These findings allude to a conserved mechanism for the modulation of TP53- dependent pro-survival functions by viral oncoproteins and mitogenic signals to protect proliferating cells against metabolic oxidative toxicity. Moreover, we demonstrate that lentiviral-siRNA-knockdown of TIGAR expression in immunodeficient NOD/scid mice engrafted with HTLV-1+ SLB1-Green Fluorescent Protein (GFP) tumor cells effectively inhibited lymphomagenesis and CNS metastasis in vivo, suggesting that TIGAR could be a plausible target for antiviral therapy to treat HTLV-1-associated cancers

Published Date: 2024-04-29; Received Date: 2024-03-22