ANKS4B Restricts Replication of Zika Virus by Downregulating the Autophagy.

Quanshi Lin,Chao Liu,Zhiting Huo,Xin Luo,Yanxia Huang,Cancan Chen,Shili Zhou,Ping Zhang,Junfang He

doi:10.3389/fmicb.2020.01745

Quanshi Lin, Chao Liu + Show 7 more

Open Access

https://doi.org/10.3389/fmicb.2020.01745

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Abstract

Infection of Zika virus (ZIKV) has become a severe threaten to global health while no specific drug is available. In this study, we explored the relationship between ZIKV and a cellular protein, ankyrin repeat and sterile motif domain containing 4b (ANKS4B). Our data revealed that the expression of ANKS4B in cultured cells and in neonatal mice was downregulated by ZIKV infection. The reduction of ANKS4B upon ZIKV infection was caused by decrease of two hepatocyte nuclear factors HNF1α and HNF4α. Through CRISPR/Cas9 gene editing system, we generated two ANKS4B knockout (KO) cell clones in A549 and Huh7 cells respectively. In the ANKS4B-KO cells, the viral replication levels including viral RNA, protein, and titer were significantly enhanced, which was reversed by trans-complementation of ANKS4B. ANKS4B did not affect the viral entry step, but impaired the autophagy induced by ZIKV infection. Furthermore, our data showed that inhibition of autophagy led to similar replication levels of ZIKV in ANKS4B-sufficient and ANKS4B-deficient cells, suggesting the antiviral effect of ANKS4B relied on its modulation on the autophagy. Therefore, our work identified ANKS4B as a new restriction factor of ZIKV.

Highlights

Zika virus (ZIKV) is a re-emerging arbovirus in the genus Flavivirus of the family Flaviviridae (Musso and Gubler, 2016)
As ANKS4B has been reported to be abundantly expressed in liver, kidney, small intestine, and colon (Johnston et al, 2004), we examined whether ZIKV infection had an impact on ANKS4B expression in a hepatoma cell line, Huh7
As the endoplasmic reticulum (ER) stress induced by ZIKV infection is associated with autophagy (Ojha et al, 2019), we explored whether ANKS4B has an impact on the autophagy induced by ZIKV

Summary

Introduction

Zika virus (ZIKV) is a re-emerging arbovirus in the genus Flavivirus of the family Flaviviridae (Musso and Gubler, 2016). ZIKV infection may be asymptomatic and symptomatic. The symptoms are usually mild and similar to other infectious diseases such as dengue fever, including fever, rash, arthralgia, and conjunctivitis (Petersen et al, 2016; Pierson and Diamond, 2018; Moutailler et al, 2019). ZIKV infection might cause severe symptoms, including GuillainBarré syndrome and congenital microcephaly (Pierson and Diamond, 2018). The genome of ZIKV is a positive-strand single-stranded RNA of 11 kb in length (Weaver et al, 2016; Pierson and Diamond, 2018). Once the viral genome enters cell cytoplasm, it directly encodes a polyprotein, which is processed by viral and host proteases into three structural proteins (capsid, premembrane, and envelope) and seven nonstructural proteins

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