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

Donghyuk Shin, Rukmini Mukherjee, Diana Grewe, Denisa Bojkova, Kheewoong Baek, Anshu Bhattacharya, Laura Schulz, Marek Widera, Ahmad Reza Mehdipour, Georg Tascher, Paul P. Geurink, Alexander Wilhelm, Gerbrand J. van der Heden van Noort, Huib Ovaa, Stefan Müller, Klaus Peter Knobeloch, Krishnaraj Rajalingam, Brenda A. Schulman, Jindrich Cinatl, Gerhard HummerSandra Ciesek, Ivan Dikic

Research output: Contribution to journalArticlepeer-review

71 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)657-662
Number of pages6
JournalNature
Volume587
Issue number7835
DOIs
Publication statusPublished - 2020 Nov 26

Bibliographical note

Funding Information:
Acknowledgements We thank A. Gubas, C. Joazeiro, D. Hoeller and K. Koch for critical comments on the manuscript. We also thank Swiss Light Source (SLS) for providing special beam time for this project during the peak of the COVID-19 pandemic in Switzerland and W. Meitian and O. Vincent for providing on-site support during the data collection. We thank the Quantitative Proteomics Unit (IBCII, Goethe University Frankfurt) for support and expertise in sample preparation, LC–MS instrumentation and data analysis. This work was supported by the DFG-funded Collaborative Research Centre on Selective Autophagy (SFB 1177), by the Max Planck Society, by NWO (H.O. and G.J.v.d.H.v.N.) by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 789016) to B.A.S., LYSFOR2625 (DFG) to A.B. and (grant agreement no. 742720) to I.D., by the grants from Else Kroener Fresenius Stiftung, Dr. Rolf M. Schwiete Stiftung, and by internal IBC2 funds to I.D.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

All Science Journal Classification (ASJC) codes

  • General

Fingerprint Dive into the research topics of 'Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity'. Together they form a unique fingerprint.

Cite this