Topoisomerase 2β-dependent nuclear DNA damage shapes extracellular growth factor responses via dynamic AKT phosphorylation to control virus latency

• Published in: Molecular cell Vol. 74; no. 3; pp. 466 - 480.e4
• Main Authors: Hu, Hui-Lan, Shiflett, Lora A., Kobayashi, Mariko, Chao, Moses V., Wilson, Angus C., Mohr, Ian, Huang, Tony T.
• Format: Journal Article
• Language: English
• Published: 28.03.2019
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.02.032

The mTOR pathway integrates both extracellular and intracellular signals and serves as a central regulator of cell metabolism, growth, survival and stress responses. Neurotropic viruses, such as herpes simplex virus-1 (HSV-1), also rely on cellular AKT-mTORC1 signaling to achieve viral latency. Here, we define a novel genotoxic response whereby spatially separated signals initiated by extracellular neurotrophic factors and nuclear DNA damage are integrated by the AKT-mTORC1 pathway. We demonstrate that endogenous DNA double-strand breaks (DSBs) mediated by Topoisomerase 2β-DNA cleavage complex (TOP2βcc) intermediates are required to achieve AKT-mTORC1 signaling and maintain HSV-1 latency in neurons. Suppression of host DNA repair pathways that remove TOP2βcc trigger HSV-1 reactivation. Moreover, perturbation of AKT phosphorylation dynamics by downregulating the PHLPP1 phosphatase led to AKT mis-localization and disruption of DSB-induced HSV-1 reactivation. Thus, the cellular genome integrity and environmental inputs are consolidated and co-opted by a latent virus to balance lifelong infection with transmission. How viral latency is regulated by growth factor signaling is not well understood. Hu et al. show that a topoisomerase 2β-dependent endogenous DNA damage signal feeds into the AKT-mTORC1 pathway to control HSV-1 latency in neurons.