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MERS-CoV ORF4b employs an unusual binding mechanism to target IMPα and block innate immunity

DOI: 10.1038/s41467-022-28851-2 DOI Help

Authors: Thilini S. Munasinghe (Charles Sturt University) , Megan R. Edwards (Georgia State University) , Sofiya Tsimbalyuk (Charles Sturt University) , Olivia A. Vogel (Georgia State University) , Kate M. Smith (Swiss Light Source) , Murray Stewart (MRC Laboratory of Molecular Biology) , Justin K. Foster (Charles Sturt University) , Loretta A. Bosence (Charles Sturt University) , David Aragao (Diamond Light Source) , Justin A. Roby (Charles Sturt University) , Christopher F. Basler (Georgia State University; Icahn School of Medicine at Mount Sinai) , Jade K. Forwood (Charles Sturt University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 13

State: Published (Approved)
Published: March 2022

Open Access Open Access

Abstract: The MERS coronavirus (MERS-CoV) is a highly pathogenic, emerging virus that produces accessory proteins to antagonize the host innate immune response. The MERS-CoV ORF4b protein has been shown to bind preferentially to the nuclear import adapter IMPα3 in infected cells, thereby inhibiting NF-κB-dependent innate immune responses. Here, we report high-resolution structures of ORF4b bound to two distinct IMPα family members. Each exhibit highly similar binding mechanisms that, in both cases, lack a prototypical Lys bound at their P2 site. Mutations within the NLS region dramatically alter the mechanism of binding, which reverts to the canonical P2 Lys binding mechanism. Mutational studies confirm that the novel binding mechanism is important for its nuclear import, IMPα interaction, and inhibition of innate immune signaling pathways. In parallel, we determined structures of the nuclear binding domain of NF-κB component p50 bound to both IMPα2 and α3, demonstrating that p50 overlaps with the ORF4b binding sites, suggesting a basis for inhibition. Our results provide a detailed structural basis that explains how a virus can target the IMPα nuclear import adapter to impair immunity, and illustrate how small mutations in ORF4b, like those found in closely related coronaviruses such as HKU5, change the IMPα binding mechanism.

Journal Keywords: Viral infection; Virus–host interactions

Diamond Keywords: MERS-CoV; Viruses

Subject Areas: Biology and Bio-materials

Facility: MX2 at Australian Synchrotron

Added On: 28/03/2022 11:53


Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

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