ORF6 protein of SARS-CoV-2 inhibits TRIM25 mediated RIG-I ubiquitination to mitigate type I IFN induction
ORF6 protein of SARS-CoV-2 inhibits TRIM25 mediated RIG-I ubiquitination to mitigate type I IFN induction
Abstract Evasion and antagonism of host cellular immunity upon SARS-CoV-2 infection confers a profound replication advantage on the virus and contributes to COVID-19 pathogenesis. We explored the ability of different SARS-CoV-2 proteins to antagonize the host innate immune system and found that the ORF6 protein mitigated type-I IFN (interferon) induction and downstream IFN signaling. Our findings also corroborated previous reports that ORF6 blocks the nuclear import of IRF3 and STAT1 to inhibit IFN induction and signaling. Here we show that ORF6 directly interacts with RIG-I and blocks downstream type-I IFN induction and signaling by inhibiting K-63 linked ubiquitination of RIG-I by the E3 Ligase TRIM25. This involves ORF6-mediated targeting of TRIM25 for degradation, also observed during SARS-CoV-2 infection. The type-I IFN antagonistic activity of ORF6 was mapped to its C-terminal cytoplasmic tail, specifically to amino acid residues 52-61. Overall, we provide new insights into how the SARS-CoV-2 ORF6 protein inhibits type I-IFN induction and signaling through distinct mechanisms.
Narayan Rohan、Sharma Mansi、Tripathi Shashank、Khatun Oyahida
Emerging Viral Pathogens Laboratory, Centre for Infectious Disease Research, Indian Institute of Science||Microbiology & Cell Biology Department, Biological Sciences Division, Indian Institute of ScienceEmerging Viral Pathogens Laboratory, Centre for Infectious Disease Research, Indian Institute of Science||Microbiology & Cell Biology Department, Biological Sciences Division, Indian Institute of ScienceEmerging Viral Pathogens Laboratory, Centre for Infectious Disease Research, Indian Institute of Science||Microbiology & Cell Biology Department, Biological Sciences Division, Indian Institute of ScienceEmerging Viral Pathogens Laboratory, Centre for Infectious Disease Research, Indian Institute of Science||Microbiology & Cell Biology Department, Biological Sciences Division, Indian Institute of Science
基础医学分子生物学微生物学
SARS-CoV-2COVID-19Innate ImmunityType-I IFNORF6RIG-IUbiquitinationTRIM25
Narayan Rohan,Sharma Mansi,Tripathi Shashank,Khatun Oyahida.ORF6 protein of SARS-CoV-2 inhibits TRIM25 mediated RIG-I ubiquitination to mitigate type I IFN induction[EB/OL].(2025-03-28)[2025-05-11].https://www.biorxiv.org/content/10.1101/2022.05.05.490850.点此复制
评论