Your browser doesn't support javascript.
Decoupling SARS-CoV-2 ORF6 localization and interferon antagonism.
Wong, Hoi Tong; Cheung, Victoria; Salamango, Daniel J.
  • Wong HT; Department of Microbiology and Immunology, Stony Brook University, Stony Brook, New York 11794, USA.
  • Cheung V; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 1194, USA.
  • Salamango DJ; Department of Microbiology and Immunology, Stony Brook University, Stony Brook, New York 11794, USA.
J Cell Sci ; 135(6)2022 03 15.
Article in English | MEDLINE | ID: covidwho-1699626
ABSTRACT
Like many pathogenic viruses, SARS-CoV-2 must overcome interferon (IFN)-mediated host defenses for infection establishment. To achieve this, SARS-CoV-2 deploys overlapping mechanisms to antagonize IFN production and signaling. The strongest IFN antagonist is the accessory protein ORF6, which localizes to multiple membranous compartments, including the nuclear envelope, where it directly binds nuclear pore component Nup98-Rae1 to inhibit nuclear translocation of activated STAT1 and IRF3 transcription factors. However, this direct cause-and-effect relationship between ORF6 localization and IFN antagonism has yet to be explored experimentally. Here, we use extensive mutagenesis studies to define the structural determinants required for steady-state localization and demonstrate that mis-localized ORF6 variants still potently inhibit nuclear trafficking and IFN signaling. Additionally, expression of a peptide that mimics the ORF6-Nup98 interaction domain robustly blocked nuclear trafficking. Furthermore, pharmacologic and mutational approaches combined to suggest that ORF6 is likely a peripheral membrane protein, as opposed to being a transmembrane protein as previously speculated. Thus, ORF6 localization and IFN antagonism are independent activities, which raises the possibility that ORF6 may have additional functions within membrane networks to enhance virus replication. This article has an associated First Person interview with the first author of the paper.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Topics: Variants Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: Jcs.259666

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Topics: Variants Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: Jcs.259666