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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.<\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.01028-23","type":"journal-article","created":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T13:02:29Z","timestamp":1695992549000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":24,"title":["EGR1 functions as a new host restriction factor for SARS-CoV-2 to inhibit virus replication through the E3 ubiquitin ligase MARCH8"],"prefix":"10.1128","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2938-4787","authenticated-orcid":false,"given":"Yinghua","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases and Center of Infectious Diseases and Pathogen Biology, Key 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