Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport

Gao，Xiaopan1; Tian，Huabin2; Zhu，Kaixiang1; Li，Qing2,3; Hao，Wei1; Wang，Linyue1; Qin，Bo1; Deng，Hongyu2,3; Cui，Sheng1,4

2022-12-01

10.1038/s41467-022-32489-5

Nature Communications   影响因子和分区

2041-1723

The emergence of heavily mutated SARS-CoV-2 variants of concern (VOCs) place the international community on high alert. In addition to numerous mutations that map in the spike protein of VOCs, expression of the viral accessory proteins ORF6 and ORF9b also elevate; both are potent interferon antagonists. Here, we present the crystal structures of Rae1-Nup98 in complex with the C-terminal tails (CTT) of SARS-CoV-2 and SARS-CoV ORF6 to 2.85 Å and 2.39 Å resolution, respectively. An invariant methionine (M) 58 residue of ORF6 CTT extends its side chain into a hydrophobic cavity in the Rae1 mRNA binding groove, resembling a bolt-fitting-hole; acidic residues flanking M58 form salt-bridges with Rae1. Our mutagenesis studies identify key residues of ORF6 important for its interaction with Rae1-Nup98 in vitro and in cells, of which M58 is irreplaceable. Furthermore, we show that ORF6-mediated blockade of mRNA and STAT1 nucleocytoplasmic transport correlate with the binding affinity between ORF6 and Rae1-Nup98. Finally, binding of ORF6 to Rae1-Nup98 is linked to ORF6-induced interferon antagonism. Taken together, this study reveals the molecular basis for the antagonistic function of Sarbecovirus ORF6, and implies a strategy of using ORF6 CTT-derived peptides for immunosuppressive drug development.

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通讯

Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences[2021-I2M-1-037] ; National Key Research and Development Program of China["2016YFD0500300","2019YFC0840602"] ; National Natural Science Foundation of China["81971985","81772207","81572005","81921005","31900131"] ; Chinese Academy of Sciences["XDB37030205","KJZD-SW-L05"] ; Ministry of Science and Technology[2021YFA1300802] ; Beijing Natural Science Foundation[5222024]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000840984400010

NATURE PORTFOLIO

2-s2.0-85136073947

Scopus

1.NHC Key Laboratory of Systems Biology of Pathogens,Institute of Pathogen Biology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,100730,China
2.CAS Key Laboratory of Infection and Immunity,CAS Center for Excellence in Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing,100101,China
3.University of Chinese Academy of Sciences,Beijing,100049,China
4.Sanming Project of Medicine in Shenzhen,National Clinical Research Center for Infectious Diseases,Shenzhen Third People’s Hospital,Southern University of Science and Technology,Shenzhen,China

Gao，Xiaopan,Tian，Huabin,Zhu，Kaixiang,et al. Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport[J]. Nature Communications,2022,13(1).

Gao，Xiaopan.,Tian，Huabin.,Zhu，Kaixiang.,Li，Qing.,Hao，Wei.,...&Cui，Sheng.(2022).Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport.Nature Communications,13(1).

Gao，Xiaopan,et al."Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport".Nature Communications 13.1(2022).