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Article ; Online: Nidovirus papain-like proteases: multifunctional enzymes with protease, deubiquitinating and deISGylating activities.

Mielech, Anna M / Chen, Yafang / Mesecar, Andrew D / Baker, Susan C

2014 Volume 194, Page(s) 184–190

Abstract: Coronaviruses and arteriviruses, members of the order Nidovirales, are positive strand RNA viruses that encode large replicase polyproteins that are processed by viral proteases to generate the nonstructural proteins which mediate viral RNA synthesis. ... ...

Abstract	Coronaviruses and arteriviruses, members of the order Nidovirales, are positive strand RNA viruses that encode large replicase polyproteins that are processed by viral proteases to generate the nonstructural proteins which mediate viral RNA synthesis. The viral papain-like proteases (PLPs) are critical for processing the amino-terminal end of the replicase and are attractive targets for antiviral therapies. With the analysis of the papain-like protease of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), came the realization of the multifunctional nature of these enzymes. Structural and enzymatic studies revealed that SARS-CoV PLpro can act as both a protease to cleave peptide bonds and also as a deubiquitinating (DUB) enzyme to cleave the isopeptide bonds found in polyubiquitin chains. Furthermore, viral DUBs can also remove the protective effect of conjugated ubiquitin-like molecules such as interferon stimulated gene 15 (ISG15). Extension of these studies to other coronaviruses and arteriviruses led to the realization that viral protease/DUB activity is conserved in many family members. Overexpression studies revealed that viral protease/DUB activity can modulate or block activation of the innate immune response pathway. Importantly, mutations that alter DUB activity but not viral protease activity have been identified and arteriviruses expressing DUB mutants stimulated higher levels of acute inflammatory cytokines after infection. Further understanding of the multifunctional nature of the Nidovirus PLP/DUBs may facilitate vaccine development. Here, we review studies describing the PLPs' enzymatic activity and their role in virus pathogenesis.
MeSH term(s)	Multifunctional Enzymes/metabolism ; Nidovirales/enzymology ; Peptide Hydrolases/metabolism ; Ubiquitin-Specific Proteases/metabolism
Chemical Substances	Multifunctional Enzymes ; Peptide Hydrolases (EC 3.4.-) ; Ubiquitin-Specific Proteases (EC 3.4.19.12)
Keywords	covid19
Language	English
Publishing date	2014-02-07
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2014.01.025
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Article ; Online: Structure-Guided Mutagenesis Alters Deubiquitinating Activity and Attenuates Pathogenesis of a Murine Coronavirus.

Deng, Xufang / Chen, Yafang / Mielech, Anna M / Hackbart, Matthew / Kesely, Kristina R / Mettelman, Robert C / O'Brien, Amornrat / Chapman, Mackenzie E / Mesecar, Andrew D / Baker, Susan C

Journal of virology

2020 Volume 94, Issue 11

Abstract: Coronaviruses express a multifunctional papain-like protease, termed papain-like protease 2 (PLP2). PLP2 acts as a protease that cleaves the viral replicase polyprotein and as a deubiquitinating (DUB) enzyme which removes ubiquitin (Ub) moieties from ... ...

Abstract	Coronaviruses express a multifunctional papain-like protease, termed papain-like protease 2 (PLP2). PLP2 acts as a protease that cleaves the viral replicase polyprotein and as a deubiquitinating (DUB) enzyme which removes ubiquitin (Ub) moieties from ubiquitin-conjugated proteins. Previous
MeSH term(s)	Amino Acid Sequence ; Animals ; Coronavirus Infections/virology ; Host-Pathogen Interactions ; Interferon Type I/metabolism ; Macrophages/immunology ; Macrophages/metabolism ; Macrophages/virology ; Mice ; Models, Molecular ; Murine hepatitis virus/pathogenicity ; Murine hepatitis virus/physiology ; Mutagenesis ; Protein Conformation ; Structure-Activity Relationship ; Ubiquitination ; Viral Proteins/chemistry ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Virulence ; Virus Replication
Chemical Substances	Interferon Type I ; Viral Proteins
Keywords	covid19
Language	English
Publishing date	2020-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01734-19
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Article ; Online: Assessing activity and inhibition of Middle East respiratory syndrome coronavirus papain-like and 3C-like proteases using luciferase-based biosensors.

Kilianski, Andy / Mielech, Anna M / Deng, Xufang / Baker, Susan C

Journal of virology

2013 Volume 87, Issue 21, Page(s) 11955–11962

Abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) is associated with an outbreak of more than 90 cases of severe pneumonia with high mortality (greater than 50%). To date, there are no antiviral drugs or specific therapies to treat MERS-CoV. To ... ...

Abstract	Middle East respiratory syndrome coronavirus (MERS-CoV) is associated with an outbreak of more than 90 cases of severe pneumonia with high mortality (greater than 50%). To date, there are no antiviral drugs or specific therapies to treat MERS-CoV. To rapidly identify potential inhibitors of MERS-CoV replication, we expressed the papain-like protease (PLpro) and the 3-chymotrypsin-like protease (3CLpro) from MERS-CoV and developed luciferase-based biosensors to monitor protease activity in cells. We show that the expressed MERS-CoV PLpro recognizes and processes the canonical CoV-PLpro cleavage site RLKGG in the biosensor. However, existing CoV PLpro inhibitors were unable to block MERS-CoV PLpro activity, likely due to the divergence of the amino acid sequence in the drug binding site. To investigate MERS-CoV 3CLpro activity, we expressed the protease in context with flanking nonstructural protein 4 (nsp4) and the amino-terminal portion of nsp6 and detected processing of the luciferase-based biosensors containing the canonical 3CLpro cleavage site VRLQS. Importantly, we found that a small-molecule inhibitor that blocks replication of severe acute respiratory syndrome (SARS) CoV and murine CoV also inhibits the activity of MERS-CoV 3CLpro. Overall, the protease expression and biosensor assays developed here allow for rapid evaluation of viral protease activity and the identification of protease inhibitors. These biosensor assays can now be used to screen for MERS-CoV-specific or broad-spectrum coronavirus PLpro and 3CLpro inhibitors.
MeSH term(s)	3C Viral Proteases ; Antiviral Agents/isolation & purification ; Antiviral Agents/metabolism ; Biosensing Techniques/methods ; Cell Line ; Coronavirus/drug effects ; Coronavirus/enzymology ; Cysteine Endopeptidases/metabolism ; Drug Evaluation, Preclinical/methods ; Genes, Reporter ; Humans ; Luciferases/analysis ; Luciferases/genetics ; Protease Inhibitors/isolation & purification ; Protease Inhibitors/metabolism ; Viral Proteins/antagonists & inhibitors ; Viral Proteins/metabolism
Chemical Substances	Antiviral Agents ; Protease Inhibitors ; Viral Proteins ; Luciferases (EC 1.13.12.-) ; Cysteine Endopeptidases (EC 3.4.22.-) ; 3C Viral Proteases (EC 3.4.22.28)
Keywords	covid19
Language	English
Publishing date	2013-08-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.02105-13
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Article: Nidovirus papain-like proteases: Multifunctional enzymes with protease, deubiquitinating and deISGylating activities

Mielech, Anna M / Chen, Yafang / Mesecar, Andrew D / Baker, Susan C

Virus research. 2014 Dec. 19, v. 194

2014

Abstract	Coronaviruses and arteriviruses, members of the order Nidovirales, are positive strand RNA viruses that encode large replicase polyproteins that are processed by viral proteases to generate the nonstructural proteins which mediate viral RNA synthesis. The viral papain-like proteases (PLPs) are critical for processing the amino-terminal end of the replicase and are attractive targets for antiviral therapies. With the analysis of the papain-like protease of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), came the realization of the multifunctional nature of these enzymes. Structural and enzymatic studies revealed that SARS-CoV PLpro can act as both a protease to cleave peptide bonds and also as a deubiquitinating (DUB) enzyme to cleave the isopeptide bonds found in polyubiquitin chains. Furthermore, viral DUBs can also remove the protective effect of conjugated ubiquitin-like molecules such as interferon stimulated gene 15 (ISG15). Extension of these studies to other coronaviruses and arteriviruses led to the realization that viral protease/DUB activity is conserved in many family members. Overexpression studies revealed that viral protease/DUB activity can modulate or block activation of the innate immune response pathway. Importantly, mutations that alter DUB activity but not viral protease activity have been identified and arteriviruses expressing DUB mutants stimulated higher levels of acute inflammatory cytokines after infection. Further understanding of the multifunctional nature of the Nidovirus PLP/DUBs may facilitate vaccine development. Here, we review studies describing the PLPs’ enzymatic activity and their role in virus pathogenesis.
Keywords	RNA ; Severe acute respiratory syndrome coronavirus ; cytokines ; enzyme activity ; genes ; innate immunity ; interferons ; mutants ; mutation ; pathogenesis ; polyproteins ; protective effect ; proteinases ; vaccine development ; viral nonstructural proteins ; covid19
Language	English
Dates of publication	2014-1219
Size	p. 184-190.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2014.01.025
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Article ; Online: X-ray Structural and Functional Studies of the Three Tandemly Linked Domains of Non-structural Protein 3 (nsp3) from Murine Hepatitis Virus Reveal Conserved Functions.

Chen, Yafang / Savinov, Sergey N / Mielech, Anna M / Cao, Thu / Baker, Susan C / Mesecar, Andrew D

The Journal of biological chemistry

2015 Volume 290, Issue 42, Page(s) 25293–25306

Abstract: Murine hepatitis virus (MHV) has long served as a model system for the study of coronaviruses. Non-structural protein 3 (nsp3) is the largest nsp in the coronavirus genome, and it contains multiple functional domains that are required for coronavirus ... ...

Abstract	Murine hepatitis virus (MHV) has long served as a model system for the study of coronaviruses. Non-structural protein 3 (nsp3) is the largest nsp in the coronavirus genome, and it contains multiple functional domains that are required for coronavirus replication. Despite the numerous functional studies on MHV and its nsp3 domain, the structure of only one domain in nsp3, the small ubiquitin-like domain 1 (Ubl1), has been determined. We report here the x-ray structure of three tandemly linked domains of MHV nsp3, including the papain-like protease 2 (PLP2) catalytic domain, the ubiquitin-like domain 2 (Ubl2), and a third domain that we call the DPUP (domain preceding Ubl2 and PLP2) domain. DPUP has close structural similarity to the severe acute respiratory syndrome coronavirus unique domain C (SUD-C), suggesting that this domain may not be unique to the severe acute respiratory syndrome coronavirus. The PLP2 catalytic domain was found to have both deubiquitinating and deISGylating isopeptidase activities in addition to proteolytic activity. A computationally derived model of MHV PLP2 bound to ubiquitin was generated, and the potential interactions between ubiquitin and PLP2 were probed by site-directed mutagenesis. These studies extend substantially our structural knowledge of MHV nsp3, providing a platform for further investigation of the role of nsp3 domains in MHV viral replication.
MeSH term(s)	Amino Acid Sequence ; Crystallography, X-Ray ; Molecular Sequence Data ; Murine hepatitis virus/chemistry ; Protein Conformation ; Sequence Homology, Amino Acid ; Substrate Specificity ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/physiology
Chemical Substances	Viral Nonstructural Proteins
Keywords	covid19
Language	English
Publishing date	2015-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M115.662130
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Article ; Online: Coronavirus nonstructural protein 15 mediates evasion of dsRNA sensors and limits apoptosis in macrophages.

Deng, Xufang / Hackbart, Matthew / Mettelman, Robert C / O'Brien, Amornrat / Mielech, Anna M / Yi, Guanghui / Kao, C Cheng / Baker, Susan C

Proceedings of the National Academy of Sciences of the United States of America

2017 Volume 114, Issue 21, Page(s) E4251–E4260

Abstract: Coronaviruses are positive-sense RNA viruses that generate double-stranded RNA (dsRNA) intermediates during replication, yet evade detection by host innate immune sensors. Here we report that coronavirus nonstructural protein 15 (nsp15), an ... ...

Abstract	Coronaviruses are positive-sense RNA viruses that generate double-stranded RNA (dsRNA) intermediates during replication, yet evade detection by host innate immune sensors. Here we report that coronavirus nonstructural protein 15 (nsp15), an endoribonuclease, is required for evasion of dsRNA sensors. We evaluated two independent nsp15 mutant mouse coronaviruses, designated N15m1 and N15m3, and found that these viruses replicated poorly and induced rapid cell death in mouse bone marrow-derived macrophages. Infection of macrophages with N15m1, which expresses an unstable nsp15, or N15m3, which expresses a catalysis-deficient nsp15, activated MDA5, PKR, and the OAS/RNase L system, resulting in an early, robust induction of type I IFN, PKR-mediated apoptosis, and RNA degradation. Immunofluorescence imaging of nsp15 mutant virus-infected macrophages revealed significant dispersal of dsRNA early during infection, whereas in WT virus-infected cells, the majority of the dsRNA was associated with replication complexes. The loss of nsp15 activity also resulted in greatly attenuated disease in mice and stimulated a protective immune response. Taken together, our findings demonstrate that coronavirus nsp15 is critical for evasion of host dsRNA sensors in macrophages and reveal that modulating nsp15 stability and activity is a strategy for generating live-attenuated vaccines.
MeSH term(s)	Animals ; Apoptosis/genetics ; Apoptosis/immunology ; Cell Line ; Coronavirus/genetics ; Coronavirus/immunology ; Coronavirus Infections/pathology ; Coronavirus Infections/virology ; Cricetinae ; Endoribonucleases/metabolism ; Enzyme Activation/genetics ; Immunity, Innate/immunology ; Interferon Type I/genetics ; Interferon Type I/immunology ; Interferon-Induced Helicase, IFIH1/metabolism ; Macrophages/immunology ; Macrophages/virology ; Mice ; RNA, Double-Stranded/genetics ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/immunology
Chemical Substances	Interferon Type I ; RNA, Double-Stranded ; Viral Nonstructural Proteins ; nonstructural protein, coronavirus ; Endoribonucleases (EC 3.1.-) ; 2-5A-dependent ribonuclease (EC 3.1.26.-) ; Ifih1 protein, mouse (EC 3.6.1.-) ; Interferon-Induced Helicase, IFIH1 (EC 3.6.4.13)
Keywords	covid19
Language	English
Publishing date	2017-05-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1618310114
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Article ; Online: Catalytic function and substrate specificity of the papain-like protease domain of nsp3 from the Middle East respiratory syndrome coronavirus.

Báez-Santos, Yahira M / Mielech, Anna M / Deng, Xufang / Baker, Susan / Mesecar, Andrew D

Journal of virology

2014 Volume 88, Issue 21, Page(s) 12511–12527

Abstract: Unlabelled: The papain-like protease (PLpro) domain from the deadly Middle East respiratory syndrome coronavirus (MERS-CoV) was overexpressed and purified. MERS-CoV PLpro constructs with and without the putative ubiquitin-like (UBL) domain at the N ... ...

Abstract	Unlabelled: The papain-like protease (PLpro) domain from the deadly Middle East respiratory syndrome coronavirus (MERS-CoV) was overexpressed and purified. MERS-CoV PLpro constructs with and without the putative ubiquitin-like (UBL) domain at the N terminus were found to possess protease, deubiquitinating, deISGylating, and interferon antagonism activities in transfected HEK293T cells. The quaternary structure and substrate preferences of MERS-CoV PLpro were determined and compared to those of severe acute respiratory syndrome coronavirus (SARS-CoV) PLpro, revealing prominent differences between these closely related enzymes. Steady-state kinetic analyses of purified MERS-CoV and SARS-CoV PLpros uncovered significant differences in their rates of hydrolysis of 5-aminomethyl coumarin (AMC) from C-terminally labeled peptide, ubiquitin, and ISG15 substrates, as well as in their rates of isopeptide bond cleavage of K48- and K63-linked polyubiquitin chains. MERS-CoV PLpro was found to have 8-fold and 3,500-fold higher catalytic efficiencies for hydrolysis of ISG15-AMC than for hydrolysis of the Ub-AMC and Z-RLRGG-AMC substrates, respectively. A similar trend was observed for SARS-CoV PLpro, although it was much more efficient than MERS-CoV PLpro toward ISG15-AMC and peptide-AMC substrates. MERS-CoV PLpro was found to process K48- and K63-linked polyubiquitin chains at similar rates and with similar debranching patterns, producing monoubiquitin species. However, SARS-CoV PLpro much preferred K48-linked polyubiquitin chains to K63-linked chains, and it rapidly produced di-ubiquitin molecules from K48-linked chains. Finally, potent inhibitors of SARS-CoV PLpro were found to have no effect on MERS-CoV PLpro. A homology model of the MERS-CoV PLpro structure was generated and compared to the X-ray structure of SARS-CoV PLpro to provide plausible explanations for differences in substrate and inhibitor recognition. Importance: Unlocking the secrets of how coronavirus (CoV) papain-like proteases (PLpros) perform their multifunctional roles during viral replication entails a complete mechanistic understanding of their substrate recognition and enzymatic activities. We show that the PLpro domains from the MERS and SARS coronaviruses can recognize and process the same substrates, but with different catalytic efficiencies. The differences in substrate recognition between these closely related PLpros suggest that neither enzyme can be used as a generalized model to explain the kinetic behavior of all CoV PLpros. As a consequence, decoding the mechanisms of PLpro-mediated antagonism of the host innate immune response and the development of anti-CoV PLpro enzyme inhibitors will be a challenging undertaking. The results from this study provide valuable information for understanding how MERS-CoV PLpro-mediated antagonism of the host innate immune response is orchestrated, as well as insight into the design of inhibitors against MERS-CoV PLpro.
MeSH term(s)	Cell Line ; Cloning, Molecular ; Gene Expression ; Humans ; Kinetics ; Middle East Respiratory Syndrome Coronavirus/enzymology ; Middle East Respiratory Syndrome Coronavirus/genetics ; Peptide Hydrolases/chemistry ; Peptide Hydrolases/genetics ; Peptide Hydrolases/metabolism ; Protein Structure, Quaternary ; RNA-Dependent RNA Polymerase/chemistry ; RNA-Dependent RNA Polymerase/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/isolation & purification ; Recombinant Proteins/metabolism ; Substrate Specificity ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Nsp3 protein, Middle East respiratory syndrome coronavirus ; Recombinant Proteins ; Viral Nonstructural Proteins ; Nsp3 protein, SARS-CoV (EC 2.7.7.48) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; Peptide Hydrolases (EC 3.4.-)
Keywords	covid19
Language	English
Publishing date	2014-08-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01294-14
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Article: MERS-CoV papain-like protease has deISGylating and deubiquitinating activities

Mielech, Anna M / Kilianski, Andy / Baez-Santos, Yahira M / Mesecar, Andrew D / Baker, Susan C

Virology. 2014 Feb., v. 450-451

2014

Abstract: Coronaviruses encode papain-like proteases (PLpro) that are often multifunctional enzymes with protease activity to process the viral replicase polyprotein and deubiquitinating (DUB)/deISGylating activity, which is hypothesized to modify the innate ... ...

Abstract	Coronaviruses encode papain-like proteases (PLpro) that are often multifunctional enzymes with protease activity to process the viral replicase polyprotein and deubiquitinating (DUB)/deISGylating activity, which is hypothesized to modify the innate immune response to infection. Here, we investigate the predicted DUB activity of the PLpro domain of the recently described Middle East Respiratory Syndrome Coronavirus (MERS-CoV). We found that expression of MERS-CoV PLpro reduces the levels of ubiquitinated and ISGylated host cell proteins; consistent with multifunctional PLpro activity. Further, we compared the ability of MERS-CoV PLpro and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) PLpro to block innate immune signaling of proinflammatory cytokines. We show that expression of SARS-CoV and MERS-CoV PLpros blocks upregulation of cytokines CCL5, IFN-β and CXCL10 in stimulated cells. Overall these results indicate that the PLpro domains of MERS-CoV and SARS-CoV have the potential to modify the innate immune response to viral infection and contribute to viral pathogenesis.
Keywords	Coronavirus infections ; Middle East respiratory syndrome coronavirus ; Severe acute respiratory syndrome coronavirus ; chemokine CCL5 ; chemokine CXCL10 ; enzyme activity ; innate immunity ; interferon-beta ; pathogenesis ; polyproteins ; proteinases ; covid19
Language	English
Dates of publication	2014-02
Size	p. 64-70.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2013.11.040
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Article ; Online: MERS-CoV papain-like protease has deISGylating and deubiquitinating activities.

Mielech, Anna M / Kilianski, Andy / Baez-Santos, Yahira M / Mesecar, Andrew D / Baker, Susan C

Virology

2013 Volume 450-451, Page(s) 64–70

Abstract	Coronaviruses encode papain-like proteases (PLpro) that are often multifunctional enzymes with protease activity to process the viral replicase polyprotein and deubiquitinating (DUB)/deISGylating activity, which is hypothesized to modify the innate immune response to infection. Here, we investigate the predicted DUB activity of the PLpro domain of the recently described Middle East Respiratory Syndrome Coronavirus (MERS-CoV). We found that expression of MERS-CoV PLpro reduces the levels of ubiquitinated and ISGylated host cell proteins; consistent with multifunctional PLpro activity. Further, we compared the ability of MERS-CoV PLpro and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) PLpro to block innate immune signaling of proinflammatory cytokines. We show that expression of SARS-CoV and MERS-CoV PLpros blocks upregulation of cytokines CCL5, IFN-β and CXCL10 in stimulated cells. Overall these results indicate that the PLpro domains of MERS-CoV and SARS-CoV have the potential to modify the innate immune response to viral infection and contribute to viral pathogenesis.
MeSH term(s)	Amino Acid Sequence ; Cell Line ; Coronaviridae/chemistry ; Coronaviridae/enzymology ; Coronaviridae/genetics ; Coronaviridae Infections/genetics ; Coronaviridae Infections/metabolism ; Coronaviridae Infections/virology ; Cytokines/genetics ; Cytokines/metabolism ; Glycosylation ; Humans ; Molecular Sequence Data ; Papain/chemistry ; Papain/genetics ; Papain/metabolism ; Protein Structure, Tertiary ; SARS Virus/enzymology ; SARS Virus/genetics ; Ubiquitination ; Ubiquitins/genetics ; Ubiquitins/metabolism ; Viral Proteins/chemistry ; Viral Proteins/genetics ; Viral Proteins/metabolism
Chemical Substances	Cytokines ; Ubiquitins ; Viral Proteins ; ISG15 protein, human (60267-61-0) ; Papain (EC 3.4.22.2)
Keywords	covid19
Language	English
Publishing date	2013-12-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2013.11.040
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Article ; Online: The papain-like protease determines a virulence trait that varies among members of the SARS-coronavirus species.

Niemeyer, Daniela / Mösbauer, Kirstin / Klein, Eva M / Sieberg, Andrea / Mettelman, Robert C / Mielech, Anna M / Dijkman, Ronald / Baker, Susan C / Drosten, Christian / Müller, Marcel A

PLoS pathogens

2018 Volume 14, Issue 9, Page(s) e1007296

Abstract: SARS-coronavirus (CoV) is a zoonotic agent derived from rhinolophid bats, in which a plethora of SARS-related, conspecific viral lineages exist. Whereas the variability of virulence among reservoir-borne viruses is unknown, it is generally assumed that ... ...

Abstract	SARS-coronavirus (CoV) is a zoonotic agent derived from rhinolophid bats, in which a plethora of SARS-related, conspecific viral lineages exist. Whereas the variability of virulence among reservoir-borne viruses is unknown, it is generally assumed that the emergence of epidemic viruses from animal reservoirs requires human adaptation. To understand the influence of a viral factor in relation to interspecies spillover, we studied the papain-like protease (PLP) of SARS-CoV. This key enzyme drives the early stages of infection as it cleaves the viral polyprotein, deubiquitinates viral and cellular proteins, and antagonizes the interferon (IFN) response. We identified a bat SARS-CoV PLP, which shared 86% amino acid identity with SARS-CoV PLP, and used reverse genetics to insert it into the SARS-CoV genome. The resulting virus replicated like SARS-CoV in Vero cells but was suppressed in IFN competent MA-104 (3.7-fold), Calu-3 (2.6-fold) and human airway epithelial cells (10.3-fold). Using ectopically-expressed PLP variants as well as full SARS-CoV infectious clones chimerized for PLP, we found that a protease-independent, anti-IFN function exists in SARS-CoV, but not in a SARS-related, bat-borne virus. This PLP-mediated anti-IFN difference was seen in primate, human as well as bat cells, thus independent of the host context. The results of this study revealed that coronavirus PLP confers a variable virulence trait among members of the species SARS-CoV, and that a SARS-CoV lineage with virulent PLPs may have pre-existed in the reservoir before onset of the epidemic.
MeSH term(s)	Amino Acid Sequence ; Animals ; Chiroptera/virology ; Chlorocebus aethiops ; Coronavirus 3C Proteases ; Cysteine Endopeptidases/genetics ; Cysteine Endopeptidases/physiology ; Disease Reservoirs/virology ; HEK293 Cells ; Host Specificity ; Host-Pathogen Interactions ; Humans ; Interferons/antagonists & inhibitors ; Phylogeny ; Severe acute respiratory syndrome-related coronavirus/enzymology ; Severe acute respiratory syndrome-related coronavirus/genetics ; Severe acute respiratory syndrome-related coronavirus/pathogenicity ; Sequence Homology, Amino Acid ; Severe Acute Respiratory Syndrome/epidemiology ; Severe Acute Respiratory Syndrome/virology ; Ubiquitin/metabolism ; Vero Cells ; Viral Proteins/genetics ; Viral Proteins/physiology ; Virulence/genetics ; Virulence/physiology ; Virus Replication/genetics ; Virus Replication/physiology ; Zoonoses/epidemiology ; Zoonoses/virology
Chemical Substances	Ubiquitin ; Viral Proteins ; Interferons (9008-11-1) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
Keywords	covid19
Language	English
Publishing date	2018-09-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1007296
Database	MEDical Literature Analysis and Retrieval System OnLINE

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