TOP2β-Dependent Nuclear DNA Damage Shapes Extracellular Growth Factor Responses via Dynamic AKT Phosphorylation to Control Virus Latency.

Autor:	Hu HL; Department of Biochemistry & Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA., Shiflett LA; Department of Microbiology, NYU School of Medicine, New York, NY 10016, USA., Kobayashi M; Department of Microbiology, NYU School of Medicine, New York, NY 10016, USA., Chao MV; Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology & Neuroscience and Psychiatry, NYU School of Medicine, New York, NY 10016, USA; NYU Neuroscience Institute, NYU School of Medicine, New York, NY 10016, USA., Wilson AC; Department of Microbiology, NYU School of Medicine, New York, NY 10016, USA., Mohr I; Department of Microbiology, NYU School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Institute, NYU School of Medicine, New York, NY 10016, USA. Electronic address: ian.mohr@med.nyu.edu., Huang TT; Department of Biochemistry & Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Institute, NYU School of Medicine, New York, NY 10016, USA. Electronic address: tony.huang@nyumc.org.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2019 May 02; Vol. 74 (3), pp. 466-480.e4. Date of Electronic Publication: 2019 Mar 28.
DOI:	10.1016/j.molcel.2019.02.032
Abstrakt:	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. (Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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