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. Heden van Noort, Huib Ovaa, Stefan Müller, Klaus-Peter Knobeloch, Krishnaraj Rajalingam, Brenda A. Schulman, Jindrich Cinatl, Gerhard Hummer, Sandra Ciesek and Ivan Dikic ()
Additional contact information
Donghyuk Shin: Goethe University
Rukmini Mukherjee: Goethe University
Diana Grewe: Goethe University
Denisa Bojkova: University Hospital Frankfurt
Kheewoong Baek: Max Planck Institute of Biochemistry
Anshu Bhattacharya: Goethe University
Laura Schulz: Max Planck Institute of Biophysics
Marek Widera: University Hospital Frankfurt
Ahmad Reza Mehdipour: Max Planck Institute of Biophysics
Georg Tascher: Goethe University
Paul P. Geurink: Leiden University Medical Centre
Alexander Wilhelm: University Hospital Frankfurt
Gerbrand J. Heden van Noort: Leiden University Medical Centre
Huib Ovaa: Leiden University Medical Centre
Stefan Müller: Goethe University
Klaus-Peter Knobeloch: University of Freiburg
Krishnaraj Rajalingam: University Medical Center of the Johannes Gutenberg University Mainz
Brenda A. Schulman: Max Planck Institute of Biochemistry
Jindrich Cinatl: University Hospital Frankfurt
Gerhard Hummer: Max Planck Institute of Biophysics
Sandra Ciesek: University Hospital Frankfurt
Ivan Dikic: Goethe University

Nature, 2020, vol. 587, issue 7835, 657-662

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (10)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2601-5 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:587:y:2020:i:7835:d:10.1038_s41586-020-2601-5

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2601-5

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().