Highly pathogenic coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1,2, Middle East respiratory syndrome coronavirus (MERS-CoV)3, and SARS-CoV-14 vary in their transmissibility and pathogenicity. However, infection by all three viruses results in substantial apoptosis in cell culture5-7 and in patient tissues8-10, suggesting a potential link between apoptosis and pathogenesis of coronaviruses. Here we show that a cysteine-aspartic protease of the apoptosis cascade, caspase-6, serves as an important host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid (N) proteins, generating N fragments that serve as interferon (IFN) antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates lung pathology and body weight loss of SARS-CoV-2-infected golden Syrian hamsters and improves the survival of mouse-adapted MERS-CoV (MERS-CoVMA)-infected human DPP4 knock-in (hDPP4 KI) mice. Overall, our study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate virus replication.
This file contains Supplementary Figures 1-5 (Original images for Western blots in main figures and Extended Data figures, and Gating strategy for the flow cytometry experiment in Figure 1), Supplementary Table 1 (Putative caspase-6 cleavage motif in coronavirus N), and Supplementary Table 2 (Primer sequences).
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Chu, H., Hou, Y., Yang, D. et al. Coronaviruses exploit a host cysteine-aspartic protease for replication. Nature (2022). https://doi.org/10.1038/s41586-022-05148-4