PTEN Lipid Phosphatase Activity Enhances Dengue Virus Production through Akt/FoxO1/Maf1 Signaling
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RESEARCH ARTICLES
PTEN Lipid Phosphatase Activity Enhances Dengue Virus Production through Akt/FoxO1/Maf1 Signaling Bin Liu1 • Ting-Ting Gao1,2 • Xiao-Yu Fu1 • Zhen-Hao Xu1 • Hao Ren1 • Ping Zhao1 • Zhong-Tian Qi1 Zhao-Ling Qin1
•
Received: 10 January 2020 / Accepted: 31 July 2020 Ó Wuhan Institute of Virology, CAS 2020
Abstract Dengue virus (DENV) is an arthropod-borne viral pathogen and a global health burden. Knowledge of the DENV-host interactions that mediate virus pathogenicity remains limited. Host lipid metabolism is hijacked by DENV for virus replication in which lipid droplets (LDs) play a key role during the virus lifecycle. In this study, we reveal a novel role for phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in LDs-mediated DENV infection. We demonstrate that PTEN expression is downregulated upon DENV infection through post-transcriptional regulation and, in turn, PTEN overexpression enhances DENV replication. PTEN lipid phosphatase activity was found to decrease cellular LDs area and number through Akt/FoxO1/Maf1 signaling, which, together with autophagy, enhanced DENV replication and virus production. We therefore provide mechanistic insight into the interaction between lipid metabolism and the DENV replication cycle. Keywords Dengue virus PTEN lipid phosphatase Akt/FoxO1/Maf1 signaling Lipid metabolism
Introduction Dengue virus (DENV) is one of the most important arthropod-borne viral pathogens worldwide with 390 million people at risk annually from tropic to subtropical regions, particularly in South-east Asia and the Pacific (Bhatt et al. 2013). Approximately 50 to 100 million dengue cases and 25,000 deaths are estimated to occur each year (Bhatt et al. 2013; Murray et al. 2013). DENV
Bin Liu, Ting-Ting Gao contributed equally to this work
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12250-020-00291-6) contains supplementary material, which is available to authorized users. & Zhao-Ling Qin [email protected] & Zhong-Tian Qi [email protected] 1
Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China
2
Department of Nephrology, The Air Force Hospital from Northern Theater of PLA, Shenyang 110042, China
infections can be asymptomatic or manifest as various clinical features, ranging from atypical non-severe or nonspecific febrile illness to potentially life-threatening dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), depending on the infection status (Yung et al. 2015; Cucunawangsih and Lugito 2017). DENV belongs to the genus Flavivirus and comprises four distinct serotypes (DENV-1, DENV-2, DENV-3 and DENV-4) (Halstead 2003; Gould and Solomon 2008; Cox et al. 2012; Mustafa et al. 2015). As a member of Flaviviridae family, the virion is an enveloped particle containing a positive singlestranded RNA of * 11 kb. The viral RNA genome is translate
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