EGR1 functions as a new host restriction factor for SARS-CoV-2 to inhibit virus replication through the E3 ubiquitin ligase MARCH8

Author:

Zhao Yinghua12ORCID,Sui Liyan1,Wu Ping2,Li Letian3,Liu Li2,Ma Baohua2,Wang Wenfang4,Chi Hongmiao4,Wang Ze-Dong1,Wei Zhengkai5,Hou Zhijun2,Zhang Kaiyu1,Niu Junqi1,Jin Ningyi3,Li Chang3,Zhao Jixue6,Wang Guoqing4ORCID,Liu Quan1257ORCID

Affiliation:

1. Department of Infectious Diseases and Center of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis of the Ministry of Education, The First Hospital of Jilin University , Changchun, China

2. College of Wildlife and Protected Area, Northeast Forestry University , Harbin, China

3. Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Changchun, China

4. Department of Pathogenbiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University , Changchun, China

5. School of Life Sciences and Engineering, Foshan University , Foshan, China

6. Department of Pediatric Surgery, The First Hospital of Jilin University , Changchun, China

7. Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Institute of Zoology, Guangdong Academy of Sciences , Guangzhou, China

Abstract

ABSTRACT Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an unprecedented public health crisis worldwide. Though the host produces interferons (IFNs) and restriction factors to suppress virus infection, SARS-CoV-2 has evolved multiple strategies to inhibit the antiviral responses. Understanding host restriction factors and viral escape mechanisms is conducive to developing effective anti-SARS-CoV-2 drugs. Here, we constructed SARS-CoV-2 nucleocapsid (2N) protein- and green fluorescent protein (GFP)-stably expressing cells that were transfected with polyinosinic-polycytidylic acid (poly(I:C)) to activate IFN responses. The transcriptome analysis showed that poly(I:C)-induced IFN responses were inhibited by the SARS-CoV-2 N protein. Further analysis revealed that 2N inhibited the production of IFN-stimulated genes by suppressing early growth response gene-1 (EGR1) expression, a transcription factor that can regulate multiple cellular processes. The ectopic expression of EGR1 remarkably reduced 2N expression and suppressed SARS-CoV-2 replication. Mechanistically, EGR1 promoted expression of IFN-regulated antiviral protein (IRAV), which interacted with 2N to induce its degradation via the E3 ubiquitin ligase MARCH8 with the cargo receptor NDP52 in a lysosome-dependent pathway. MARCH8 catalyzed the K48-linked polyubiquitination of 2N at the lysine residue 143, and knockout of endogenous MARCH8 reversed IRAV-mediated 2N degradation. Additionally, the overexpression of IRAV or MARCH8 could inhibit SARS-CoV-2 replication. Our findings reveal that EGR1 is a new host restriction factor to inhibit SARS-CoV-2 replication through the E3 ubiquitin ligase MARCH8, which would contribute to understanding the pathogenesis of emerging coronaviruses. IMPORTANCE Emerging vaccine-breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight an urgent need for novel antiviral therapies. Understanding the pathogenesis of coronaviruses is critical for developing antiviral drugs. Here, we demonstrate that the SARS-CoV-2 N protein suppresses interferon (IFN) responses by reducing early growth response gene-1 (EGR1) expression. The overexpression of EGR1 inhibits SARS-CoV-2 replication by promoting IFN-regulated antiviral protein expression, which interacts with and degrades SARS-CoV-2 N protein via the E3 ubiquitin ligase MARCH8 and the cargo receptor NDP52. The MARCH8 mutants without ubiquitin ligase activity are no longer able to degrade SARS-CoV-2 N proteins, indicating that MARCH8 degrades SARS-CoV-2 N proteins dependent on its ubiquitin ligase activity. This study found a novel immune evasion mechanism of SARS-CoV-2 utilized by the N protein, which is helpful for understanding the pathogenesis of SARS-CoV-2 and guiding the design of new prevention strategies against the emerging coronaviruses.

Funder

MOST | National Natural Science Foundation of China

广东省人力资源和社会保障厅 | Guangdong Provincial Pearl River Talents Program

Scientific and Technological Research Projects of Guangzhou

MOST | National Key Research and Development Program of China

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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