FOLR1-induced folate deficiency reduces viral replication via modulating APOBEC3 family expression

Jing Wu; Yajing Han; Ruining Lyu; Fang Zhang; Na Jiang; Hongji Tao; Qiao You; Rui Zhang; Meng Yuan; Waqas Nawaz; Deyan Chen; Zhiwei Wu

doi:10.1016/j.virs.2023.04.001

June 2023

Citation: Jing Wu, Yajing Han, Ruining Lyu, Fang Zhang, Na Jiang, Hongji Tao, Qiao You, Rui Zhang, Meng Yuan, Waqas Nawaz, Deyan Chen, Zhiwei Wu. FOLR1-induced folate deficiency reduces viral replication via modulating APOBEC3 family expression .VIROLOGICA SINICA, 2023, 38(3) : 409-418. http://dx.doi.org/10.1016/j.virs.2023.04.001

FOLR1-induced folate deficiency reduces viral replication via modulating APOBEC3 family expression

Jing Wu ^a ,
Yajing Han ^e ,
Ruining Lyu ^a ,
Fang Zhang ^b ,
Na Jiang ^a ,
Hongji Tao ^a ,
Qiao You ^a ,
Rui Zhang ^a ,
Meng Yuan ^a ,
Waqas Nawaz ^f ,
Deyan Chen ^{a
,,} ,
Zhiwei Wu ^{a,c,d
,,}

a. Center for Public Health Research, Medical School of Nanjing University, Nanjing, 210093, China;
b. Department of Burn and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, 563099, China;
c. Medical School and Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China;
d. State Key Lab of Analytical Chemistry for Life Science, Nanjing University, Nanjing, 210093, China;
e. Environmental Protection Key Laboratory of Environmental Pollution Health Risk Assessment, South China Institute of Environmental Sciences, Ministry of Ecology and Environment, Guangzhou, 510535, China;
f. Hȏpital Maisonneuve-Rosemont, School of Medicine, University of Montreal, Quebec, 999040, Canada

Corresponding author: Deyan Chen, chendeyan@nju.edu.cn
Zhiwei Wu, wzhw@nju.edu.cn
Received Date: 17 October 2022
Accepted Date: 30 March 2023
Available online: 05 April 2023

Abstract

Folate receptor alpha (FOLR1) is vital for cells ingesting folate (FA). FA plays an indispensable role in cell proliferation and survival. However, it is not clear whether the axis of FOLR1/FA has a similar function in viral replication. In this study, we used vesicular stomatitis virus (VSV) to investigate the relationship between FOLR1-mediated FA deficiency and viral replication, as well as the underlying mechanisms. We discovered that FOLR1 upregulation led to the deficiency of FA in HeLa cells and mice. Meanwhile, VSV replication was notably suppressed by FOLR1 overexpression, and this antiviral activity was related to FA deficiency. Mechanistically, FA deficiency mainly upregulated apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) expression, which suppressed VSV replication in vitro and in vivo. In addition, methotrexate (MTX), an FA metabolism inhibitor, effectively inhibited VSV replication by enhancing the expression of APOBEC3B in vitro and in vivo. Overall, our present study provided a new perspective for the role of FA metabolism in viral infections and highlights the potential of MTX as a broad-spectrum antiviral agent against RNA viruses.

Electronic Supplementary Material

10.1016j.virs.2023.04.001-ESM.docx
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