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Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity
Open accessAbstract
The papain-like protease PLpro is an essential coronavirus enzyme that is 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 antiviral immune responses3–5. Here we perform biochemical, structural and functional characterization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PLpro (SCoV2-PLpro) and outline differences with SARS-CoV PLpro (SCoV-PLpro) in regulation of host interferon and NF-κB pathways. SCoV2-PLpro and SCoV-PLpro share 83% sequence identity but exhibit different host substrate preferences; SCoV2-PLpro preferentially cleaves the ubiquitin-like interferon-stimulated gene 15 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 the high affinity and specificity of these interactions. Furthermore, upon infection, SCoV2-PLpro contributes to the cleavage of ISG15 from interferon responsive factor 3 (IRF3) and attenuates type I interferon responses. Notably, inhibition of SCoV2-PLpro with GRL-0617 impairs the virus-induced cytopathogenic effect, maintains the antiviral interferon pathway and reduces viral replication in infected cells. These results highlight a potential dual therapeutic strategy in which targeting of SCoV2-PLpro can suppress SARS-CoV-2 infection and promote antiviral immunity. Biochemical, structural and functional studies on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like protease PLpro reveal that it regulates host antiviral responses by preferentially cleaving the ubiquitin-like interferon-stimulated gene 15 protein (ISG15) and identify this protease as a potential therapeutic target for coronavirus disease 2019 (COVID-19).
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Proteomics of SARS-CoV-2-infected host cells reveals therapy targets
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Metadata
- Authors
- Shin, D., Mukherjee, R., Grewe, D., Bojkova, D., Baek, K., Bhattacharya, A., Schulz, L., Widera, M., Mehdipour, A. R., Tascher, G., Geurink, P. P., Wilhelm, A., van der Heden van Noort, G. J., Ovaa, H., Müller, S., Knobeloch, K.-P., Rajalingam, K., Schulman, B. A., Cinatl, J., Hummer, G., Ciesek, S., & Dikic, I.
- Venue
- Nature
- Published
- 2020-07-29
- Volume
- 587
- Issue
- 7835
- Pages
- 657-662
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3046218096
- Cited by
- 1,177
- References
- 7
- FWCI
- 26.01
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Shin, D., Mukherjee, R., Grewe, D., Bojkova, D., Baek, K., Bhattacharya, A., Schulz, L., Widera, M., Mehdipour, A. R., Tascher, G., Geurink, P. P., Wilhelm, A., van der Heden van Noort, G. J., Ovaa, H., Müller, S., Knobeloch, K.-P., Rajalingam, K., Schulman, B. A., Cinatl, J., . . . Dikic, I. (2020). Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity. Nature. https://doi.org/10.1038/s41586-020-2601-5
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