UBXN7 facilitates SARS-CoV-2 replication via inhibiting the K48-linked ubiquitination of viral N protein

Host factor-mediated post-translational modification of coronavirus proteins has been demonstrated as an important strategy for regulating viral proliferation. Identification of key host genes involved in this process may provide potential therapeutic targets. In this study, we used the complementary reverse genetic system to determine that UBXN7 promotes SARS-CoV-2 viral double-stranded RNA (dsRNA) production and also promotes the replication of other human coronaviruses. However, UBXN7 does not affect the replication of VSV and RSV, suggesting that it may be a potential pan human coronaviral anti-infection target. Our results revealed that UBXN7 did not affect the viral invasion of cells, but instead hijacked viral genome assembly by interacting with SARS-CoV-2 N protein via its UBX domain. Further data indicated that UBXN7 inhibits K48-linked ubiquitination and proteasomal degradation of SARS-CoV-2 N protein, leading to N protein accumulation. Moreover, K257 of N protein was identified as specific target site of UBXN7 which are critical for viral replication. These findings reveal a novel relationship between host gene-mediated protein ubiquitylation and viral genome assembly, providing new strategies for potential pan-coronavirus drug design.