N protein of PEDV plays chess game with host proteins by selective autophagy

Xueying Zhai; Ning Kong; Yu Zhang; Yiyi Song; Wenzhen Qin; Xinyu Yang; Chenqian Ye; Manqing Ye; Wu Tong; Changlong Liu; Hao Zheng; Hai Yu; Wen Zhang; Xia Yang; Gaiping Zhang; Guangzhi Tong; Tongling Shan

doi:10.1080/15548627.2023.2181615

N protein of PEDV plays chess game with host proteins by selective autophagy

Autophagy. 2023 Aug;19(8):2338-2352. doi: 10.1080/15548627.2023.2181615. Epub 2023 Mar 2.

Authors

Xueying Zhai^{1

2}, Ning Kong¹, Yu Zhang³, Yiyi Song¹, Wenzhen Qin¹, Xinyu Yang¹, Chenqian Ye¹, Manqing Ye¹, Wu Tong¹, Changlong Liu¹, Hao Zheng¹, Hai Yu¹, Wen Zhang⁴, Xia Yang², Gaiping Zhang², Guangzhi Tong^{1

5}, Tongling Shan^{1

5}

Affiliations

¹ Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China.
² College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China.
³ Department of Preventive Dentistry, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
⁵ Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, China.

Abstract

Macroautophagy/autophagy is a cellular degradation and recycling process that maintains the homeostasis of organisms. The protein degradation role of autophagy has been widely used to control viral infection at multiple levels. In the ongoing evolutionary arms race, viruses have developed various ways to hijack and subvert autophagy in favor of its replication. It is still unclear exactly how autophagy affects or inhibits viruses. In this study, we have found a novel host restriction factor, HNRNPA1, that could inhibit PEDV replication by degrading viral nucleocapsid (N) protein. The restriction factor activates the HNRNPA1-MARCHF8/MARCH8-CALCOCO2/NDP52-autophagosome pathway with the help of transcription factor EGR1 targeting the HNRNPA1 promoter. HNRNPA1 could also promote the expression of IFN to facilitate the host antiviral defense response for antagonizing PEDV infection through RIGI protein interaction. During viral replication, we found that PEDV can, in contrast, degrade the host antiviral proteins HNRNPA1 and others (FUBP3, HNRNPK, PTBP1, and TARDBP) through its N protein through the autophagy pathway. These results reveal the dual function of selective autophagy in PEDV N and host proteins, which could promote the ubiquitination of viral particles and host antiviral proteins and degradation both of the proteins to regulate the relationship between virus infection and host innate immunity.Abbreviations: 3-MA: 3-methyladenine; ATG: autophagy related; Baf A1: bafilomycin A₁; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; ChIP: chromatin immunoprecipitation; Co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; GPI: glycosyl-phosphatidylinositol; hpi: hours post infection; MARCHF8/MARCH8: membrane-associated ring-CH-type finger 8; MOI: multiplicity of infection; N protein: nucleocapsid protein; PEDV: porcine epidemic diarrhea virus; siRNA: small interfering RNA; TCID₅₀: 50% tissue culture infectious doses.

Keywords: HNRNPA1; IFN; PEDV; nucleocapsid protein; selective autophagy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents
Autophagy
Coronavirus Infections*
Macroautophagy
Nucleocapsid Proteins
Porcine epidemic diarrhea virus* / genetics
Swine

Substances

Antiviral Agents
Nucleocapsid Proteins

Grants and funding

This study was supported by the National Key Research and Development Programs of China (no. 2021YFD1801102), the National Natural Science Foundation of China (no. 32102665 and 32272999), and Central Public-interest Scientific Institution Basal Research Fund (no. Y2022QC28).