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Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity

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Shin,  Donghyuk
Max Planck Fellow Group ER remodelling Group, Prof. Ivan Đikić, Max Planck Institute of Biophysics, Max Planck Society;
Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Germany;
Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Germany;

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Baek,  Kheewong
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Schulz,  Laura
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;

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Mehdipour,  Ahmad Reza
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;

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Schulman,  Brenda
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Hummer,  Gerhard
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;
Institute of Biophysics, Goethe University Frankfurt, Frankfurt am Main, Germany;

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Đikić,  Ivan
Max Planck Fellow Group ER remodelling Group, Prof. Ivan Đikić, Max Planck Institute of Biophysics, Max Planck Society;
Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Germany;
Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Germany;
Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Branch Translational Medicine and Pharmacology, Frankfurt, Germany;

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Citation

Shin, D., Mukherjee, R., Grewe, D., Bojkova, D., Baek, K., Bhattacharya, A., et al. (2020). Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity. Nature, 587(7835), 657-662. doi:10.1038/s41586-020-2601-5.


Cite as: http://hdl.handle.net/21.11116/0000-0006-C8F0-9
Abstract
The papain-like protease PLpro is an essential coronavirus enzyme required for processing viral polyproteins to generate a functional replicase complex and enable viral spread1,2. PLpro is also implicated in cleaving proteinaceous post-translational modifications on host proteins as an evasion mechanism against host anti-viral immune responses3–5. Here, we provide biochemical, structural and functional characterization of the SARS-CoV-2 PLpro (SCoV2-PLpro) and outline differences to SARS-CoV PLpro (SCoV-PLpro) in controlling host interferon (IFN) and NF-κB pathways. While SCoV2-PLpro and SCoV-PLpro share 83% sequence identity, they exhibit different host substrate preferences. In particular, SCoV2-PLpro preferentially cleaves the ubiquitin-like protein ISG15, whereas SCoV-PLpro predominantly targets ubiquitin chains. The crystal structure of SCoV2-PLpro in complex with ISG15 reveals distinctive interactions with the amino-terminal ubiquitin-like domain of ISG15, highlighting this high affinity and specificity. Furthermore, upon infection, SCoV2-PLpro contributes to the cleavage of ISG15 from interferon responsive factor 3 (IRF3) and attenuates type I interferon responses. Importantly, inhibition of SCoV2-PLpro with GRL-0617 impairs the virus-induced cytopathogenic effect, fosters the anti-viral interferon pathway and reduces viral replication in infected cells. These results highlight a dual therapeutic strategy in which targeting of SCoV2-PLpro can suppress SARS-CoV-2 infection and promote anti-viral immunity.