tetano
Editor, Senior Moderator
Nature
. 2020 Jul 29.
doi: 10.1038/s41586-020-2601-5. Online ahead of print.
Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity
Donghyuk Shin[SUP] 1 2 3 [/SUP], Rukmini Mukherjee[SUP] 1 2 [/SUP], Diana Grewe[SUP] 2 [/SUP], Denisa Bojkova[SUP] 4 [/SUP], Kheewoong Baek[SUP] 5 [/SUP], Anshu Bhattacharya[SUP] 1 2 [/SUP], Laura Schulz[SUP] 6 [/SUP], Marek Widera[SUP] 4 [/SUP], Ahmad Reza Mehdipour[SUP] 6 [/SUP], Georg Tascher[SUP] 1 [/SUP], Paul P Geurink[SUP] 7 [/SUP], Alexander Wilhelm[SUP] 4 8 [/SUP], Gerbrand J van der Heden van Noort[SUP] 7 [/SUP], Huib Ovaa[SUP] 7 [/SUP], Stefan M?ller[SUP] 1 [/SUP], Klaus-Peter Knobeloch[SUP] 9 [/SUP], Krishnaraj Rajalingam[SUP] 10 [/SUP], Brenda A Schulman[SUP] 5 [/SUP], Jindrich Cinatl[SUP] 4 [/SUP], Gerhard Hummer[SUP] 6 11 [/SUP], Sandra Ciesek[SUP] 4 8 12 [/SUP], Ivan Dikic[SUP] 13 14 15 16 [/SUP]
Affiliations
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 spread[SUP]1,2[/SUP]. PLpro is also implicated in cleaving proteinaceous post-translational modifications on host proteins as an evasion mechanism against host anti-viral immune responses[SUP]3-5[/SUP]. 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.
. 2020 Jul 29.
doi: 10.1038/s41586-020-2601-5. Online ahead of print.
Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity
Donghyuk Shin[SUP] 1 2 3 [/SUP], Rukmini Mukherjee[SUP] 1 2 [/SUP], Diana Grewe[SUP] 2 [/SUP], Denisa Bojkova[SUP] 4 [/SUP], Kheewoong Baek[SUP] 5 [/SUP], Anshu Bhattacharya[SUP] 1 2 [/SUP], Laura Schulz[SUP] 6 [/SUP], Marek Widera[SUP] 4 [/SUP], Ahmad Reza Mehdipour[SUP] 6 [/SUP], Georg Tascher[SUP] 1 [/SUP], Paul P Geurink[SUP] 7 [/SUP], Alexander Wilhelm[SUP] 4 8 [/SUP], Gerbrand J van der Heden van Noort[SUP] 7 [/SUP], Huib Ovaa[SUP] 7 [/SUP], Stefan M?ller[SUP] 1 [/SUP], Klaus-Peter Knobeloch[SUP] 9 [/SUP], Krishnaraj Rajalingam[SUP] 10 [/SUP], Brenda A Schulman[SUP] 5 [/SUP], Jindrich Cinatl[SUP] 4 [/SUP], Gerhard Hummer[SUP] 6 11 [/SUP], Sandra Ciesek[SUP] 4 8 12 [/SUP], Ivan Dikic[SUP] 13 14 15 16 [/SUP]
Affiliations
- PMID: 32726803
- DOI: 10.1038/s41586-020-2601-5
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 spread[SUP]1,2[/SUP]. PLpro is also implicated in cleaving proteinaceous post-translational modifications on host proteins as an evasion mechanism against host anti-viral immune responses[SUP]3-5[/SUP]. 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.