Loading...
AMPK protects endothelial cells against HSV-1 replication via inhibition of mTORC1 and ACC1
Doshi, Heena Spengler, Katrin Godbole, Amod Gee, Yi Sing Baell, Jonathan B. Oakhill, Jonathan Henke, Andreas Heller, Regine
Doshi, Heena
Spengler, Katrin
Godbole, Amod
Gee, Yi Sing
Baell, Jonathan B.
Oakhill, Jonathan
Henke, Andreas
Heller, Regine
Abstract
Herpes simplex virus type 1 (HSV-1) is a widespread contagious pathogen, mostly causing mild symptoms on the mucosal entry side. However, systemic distribution, in particular upon reactivation of the virus in immunocompromised patients, may trigger an innate immune response and induce damage of organs. In these conditions, HSV-1 may infect vascular endothelial cells, but little is known about the regulation of HSV-1 replication and possible defense mechanisms in these cells. The current study addresses the question of whether the host cell protein AMP-activated protein kinase (AMPK), an important metabolic sensor, can control HSV-1 replication in endothelial cells. We show that downregulation of the catalytic subunits AMPKα1 and/or AMPKα2 increased HSV-1 replication as monitored by TCID50 titrations, while a potent AMPK agonist, MK-8722, strongly inhibited it. MK-8722 induced a persistent phosphorylation of the AMPK downstream targets acetyl-CoA carboxylase (ACC) and the rapamycin-sensitive adaptor protein of mTOR (Raptor) and, related to this, impairment of ACC1-mediated lipid synthesis and the mechanistic target of the rapamycin complex-1 (mTORC1) pathway. Since blockade of mTOR by Torin-2 as well as downregulation of ACC1 by siRNA also decreased HSV-1 replication, MK-8722 is likely to exert its anti-viral effect via mTORC1 and ACC1 inhibition. Importantly, MK-8722 was able to reduce virus replication even when added after HSV-1. Together, our data highlight the importance of endothelial cells as host cells for HSV-1 replication upon systemic infection and identify AMPK, a metabolic host cell protein, as a potential target for antiviral strategies against HSV-1 infection and its severe consequences.
Keywords
HSV-1, AMPK, MK-8722, ACC, mTORC, endothelial cells, antiviral strategies
Date
2023
Type
Journal article
Journal
Book
Volume
11
Issue
5
Page Range
1-22
Article Number
ACU Department
Non-faculty
Collections
Relation URI
Event URL
Open Access Status
Published as ‘gold’ (paid) open access
License
CC BY 4.0
File Access
Open
Notes
Copyright © 2023 Doshi et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. https://creativecommons.org/licenses/by/4.0/
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. https://creativecommons.org/licenses/by/4.0/