Erp57 facilitates ZIKV-induced DNA damage via NS2B/NS3 complex formation

Yiran Wang; Dan Song; Yichen Li; Leiying Qin; Qianya Wan; Huan Hu; Mandi Wu; Yaxiu Feng; Luis Schang; Robert Weiss; Ming-Liang He

doi:10.1080/22221751.2024.2417864

Erp57 facilitates ZIKV-induced DNA damage via NS2B/NS3 complex formation

Emerg Microbes Infect. 2024 Dec;13(1):2417864. doi: 10.1080/22221751.2024.2417864. Epub 2024 Oct 28.

Authors

Yiran Wang¹, Dan Song¹, Yichen Li¹, Leiying Qin¹, Qianya Wan¹, Huan Hu¹, Mandi Wu¹, Yaxiu Feng¹, Luis Schang², Robert Weiss³, Ming-Liang He^{1

4}

Affiliations

¹ Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People's Republic of China.
² Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
³ Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
⁴ CityU Shenzhen Research Institute, Shenzhen, People's Republic of China.

Abstract

It is believed that DNA double-strand breaks induced by Zika virus (ZIKV) infection in pregnant women is a main reason of brain damage (e.g. microcephaly, severe brain malformation, and neuropathy) in newborn babies [1,2], but its underlying mechanism is poorly understood. In this study, we report that the depletion of ERp57, a member of the protein disulphide isomerase (PDI) family, leads to the limited production of ZIKV in nerve cells. ERp57 knockout not only suppresses viral induced reactive oxygen species (ROS) mediated host DNA damage, but also decreases apoptosis. Strikingly, DNA damage depends on ERp57-bridged complex formation of viral protein NS2B/NS3. LOC14, an ERp57 inhibitor, restricts ZIKV infection and virus-induced DNA damage. Our work reveals an important role of ERp57 in both ZIKV propagation and virus-induced DNA damage, suggesting a potential target against ZIKV infection.

Keywords: DNA damage; ERp57; ROS; ZIKA virus; ZIKV NS2B/NS3 complex; antiviral; apoptosis.

MeSH terms

Animals
Apoptosis
Chlorocebus aethiops
DEAD-box RNA Helicases
DNA Damage*
Humans
Nucleoside-Triphosphatase
Protein Disulfide-Isomerases* / genetics
Protein Disulfide-Isomerases* / metabolism
Reactive Oxygen Species / metabolism
Serine Endopeptidases / genetics
Serine Endopeptidases / metabolism
Vero Cells
Viral Nonstructural Proteins* / genetics
Viral Nonstructural Proteins* / metabolism
Viral Proteases
Zika Virus Infection* / metabolism
Zika Virus Infection* / virology
Zika Virus* / genetics
Zika Virus* / physiology

Substances

Viral Nonstructural Proteins
Protein Disulfide-Isomerases
PDIA3 protein, human
Serine Endopeptidases
NS2B protein, flavivirus
NS3 protein, Zika virus
Reactive Oxygen Species
Viral Proteases
Nucleoside-Triphosphatase
DEAD-box RNA Helicases

Grants and funding

The work was partially supported by grants RGC General Research Fund of Hong Kong Special Administrative Region [11104020] and Strategic funds from The City University of Hong Kong to M. He [7005874, 7020032, 9680149].