Deubiquitinating and Interferon Antagonism Activities of Coronavirus Papain-Like Proteases
Mark A. Clementz,Zhongbin Chen,Bridget S. Banach,Yanhua Wang,Li Sun,Kiira Ratia,Yahira M. Báez-Santos,Jie Wang,Jun Takayama,Arun K. Ghosh,Kui Li,Andrew D. Mesecar,Susan C. Baker +12 more
Reads0
Chats0
TLDR
The results indicated that a component of coronavirus PLP-mediated interferon antagonism was independent of protease and DUB activity, and suggest that these independent activities may provide multiple targets for antiviral therapies.Abstract:
Coronaviruses encode multifunctional proteins that are critical for viral replication and for blocking the innate immune response to viral infection. One such multifunctional domain is the coronavirus papain-like protease (PLP), which processes the viral replicase polyprotein, has deubiquitinating (DUB) activity, and antagonizes the induction of type I interferon (IFN). Here we characterized the DUB and IFN antagonism activities of the PLP domains of human coronavirus NL63 and severe acute respiratory syndrome (SARS) coronavirus to determine if DUB activity mediates interferon antagonism. We found that NL63 PLP2 deconjugated ubiquitin (Ub) and the Ub-line molecule ISG15 from cellular substrates and processed both lysine-48- and lysine-63- linked polyubiquitin chains. This PLP2 DUB activity was dependent on an intact catalytic cysteine residue. We demonstrated that in contrast to PLP2 DUB activity, PLP2-mediated interferon antagonism did not require enzymatic activity. Furthermore, addition of an inhibitor that blocks coronavirus protease/DUB activity did not abrogate interferon antagonism. These results indicated that a component of coronavirus PLP-mediated interferon antagonism was independent of protease and DUB activity. Overall, these results demonstrate the multifunctional nature of the coronavirus PLP domain as a viral protease, DUB, and IFN antagonist and suggest that these independent activities may provide multiple targets for antiviral therapies.read more
Citations
More filters
Journal ArticleDOI
Coronavirus biology and replication: implications for SARS-CoV-2.
TL;DR: The first discoveries that shape the current understanding of SARS-CoV-2 infection throughout the intracellular viral life cycle are summarized and relate that to the knowledge of coronavirus biology.
Journal ArticleDOI
The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds.
TL;DR: Targeting papain-like protease with antiviral drugs may have an advantage in not only inhibiting viral replication but also inhibiting the dysregulation of signaling cascades in infected cells that may lead to cell death in surrounding, uninfected cells.
Journal ArticleDOI
From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design
TL;DR: The crystal structure of the free SARS coronavirus Mpro and its dependence on pH is discussed, as are efforts to design inhibitors on the basis of these structures, and the role of X‐ray crystallography in structure‐assisted drug discovery against these targets is discussed.
Journal ArticleDOI
Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein
TL;DR: Through its de‐ADP‐ribosylating, de‐ubiquitinating, and de‐ISGylating activities, Nsp3 counteracts host innate immunity and is an established target for new antivirals.
Journal ArticleDOI
Human Coronaviruses: A Review of Virus-Host Interactions.
TL;DR: Various cellular processes, such as apoptosis, innate immunity, ER stress response, mitogen-activated protein kinase (MAPK) pathway and nuclear factor kappa B (NF-κB) pathway that may be modulated by HCoVs are discussed.
References
More filters
Journal ArticleDOI
UniProt: the Universal Protein knowledgebase
Rolf Apweiler,Amos Marc Bairoch,Cathy H. Wu,Winona C. Barker,Brigitte Boeckmann,Serenella Ferro,Elisabeth Gasteiger,Hongzhan Huang,Rodrigo Lopez,Michele Magrane,Maria Jesus Martin,Darren A. Natale,Claire O'Donovan,Nicole Redaschi,Lai-Su L. Yeh +14 more
TL;DR: The Swiss-Prot, TrEMBL and PIR protein database activities have united to form the Universal Protein Knowledgebase (UniProt), which is to provide a comprehensive, fully classified, richly and accurately annotated protein sequence knowledgebase, with extensive cross-references and query interfaces.
Journal ArticleDOI
Mechanisms of type-I- and type-II-interferon-mediated signalling.
TL;DR: It is anticipated that an increased understanding of the contributions of these recently identified pathways will advance current thinking about how interferons work.
Journal ArticleDOI
Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus
Etienne Meylan,Joseph Curran,Kay Hofmann,Darius Moradpour,Marco Binder,Ralf Bartenschlager,Jürg Tschopp +6 more
TL;DR: Cardif is described, a new CARD-containing adaptor protein that interacts with RIG-I and recruits IKKα, IKKβ and IKKɛ kinases by means of its C-terminal region, leading to the activation of NF-κB and IRF3.
Journal ArticleDOI
STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling.
Hiroki Ishikawa,Glen N. Barber +1 more
TL;DR: The identification of a molecule (STING; stimulator of interferon genes) that appears essential for effective innate immune signalling processes is reported, implying a potential role for the translocon in innate signalling pathways activated by select viruses as well as intracellular DNA.
Journal ArticleDOI
Bats are natural reservoirs of SARS-like coronaviruses.
Wendong Li,Zhengli Shi,Meng Yu,Wuze Ren,Craig Smith,Jonathan H. Epstein,Hanzhong Wang,Gary Crameri,Zhihong Hu,Huajun Zhang,Jianhong Zhang,Jennifer A. McEachern,Hume Field,Peter Daszak,Bryan T. Eaton,Shuyi Zhang,Lin-Fa Wang +16 more
TL;DR: It is reported that species of bats are a natural host of coronaviruses closely related to those responsible for the SARS outbreak, and these viruses display greater genetic variation than SARS-CoV isolated from humans or from civets.