Molecular mechanism underlying selective inhibition of mRNA nuclear export by herpesvirus protein ORF10

By Han Feng, Huabin Tian, Yong Wang, Qixiang Zhang, Ni Lin, Songqing Liu, Yang Yu, H. Deng, P. Gao. 2020

22 citations recorded by the source corpus.

Significance Nuclear export of host mRNAs is critical for proper cellular functions and survival. To mitigate this effort, viruses have evolved multiple strategies to inhibit this process. Distinct to the generally nonselective inhibition mechanisms, ORF10 from gammaherpesviruses blocks nuclear export of selective mRNAs by forming a complex with Rae1 (RNA export 1) and Nup98 (nucleoporin 98). Here we determine the structure of the ORF10–Rae1–Nup98 ternary complex and demonstrate that the intermolecular interactions are critical for both complex assembly and mRNA export inhibition. Moreover, we find that the ORF10-RNA direct interaction is important for ORF10-mediated mRNA export inhibition. This work is essential to understand the diversity of viral-mediated mRNA export inhibition and to design potential antiviral therapies. Viruses employ multiple strategies to inhibit host mRNA nuclear export. Distinct to the generally nonselective inhibition mechanisms, ORF10 from gammaherpesviruses inhibits mRNA export in a transcript-selective manner by interacting with Rae1 (RNA export 1) and Nup98 (nucleoporin 98). We now report the structure of ORF10 from MHV-68 (murine gammaherpesvirus 68) bound to the Rae1–Nup98 heterodimer, thereby revealing detailed intermolecular interactions. Structural and functional assays highlight that two highly conserved residues of ORF10, L60 and M413, play critical roles in both complex assembly and mRNA export inhibition. Interestingly, although ORF10 occupies the RNA-binding groove of Rae1–Nup98, the ORF10–Rae1–Nup98 ternary complex still maintains a comparable RNA-binding ability due to the ORF10–RNA direct interaction. Moreover, mutations on the RNA-binding surface of ORF10 disrupt its function of mRNA export inhibition. Our work demonstrates the molecular mechanism of ORF10-mediated selective inhibition and provides insights into the functions of Rae1–Nup98 in regulating host mRNA export.

Subfields: Epidemiology, Molecular Biology