scholarly journals Structurally Guided Removal of DeISGylase Biochemical Activity from Papain-Like Protease Originating from Middle East Respiratory Syndrome Coronavirus

2017 ◽  
Vol 91 (23) ◽  
Author(s):  
Courtney M. Daczkowski ◽  
Octavia Y. Goodwin ◽  
John V. Dzimianski ◽  
Jonathan J. Farhat ◽  
Scott D. Pegan
Keyword(s):  
Middle East ◽  
Gene Product ◽  
Isothermal Calorimetry ◽  
Middle East Respiratory Syndrome ◽  
Human Interferon ◽  
Type I ◽  
Peptide Cleavage ◽  
Terminal Domain ◽  
Immune Pathways ◽  
The Impact

ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging human pathogen that is the causative agent for Middle East respiratory syndrome (MERS). With MERS outbreaks resulting in over 35% fatalities and now spread to 27 countries, MERS-CoV poses a significant ongoing threat to global human health. As part of its viral genome, MERS-CoV encodes a papain-like protease (PLpro) that has been observed to act as a deubiquitinase and deISGylase to antagonize type I interferon (IFN-I) immune pathways. This activity is in addition to its viral polypeptide cleavage function. Although the overall impact of MERS-CoV PLpro function is observed to be essential, difficulty has been encountered in delineating the importance of its separate functions, particularly its deISGylase activity. As a result, the interface of MERS-CoV and human interferon-stimulated gene product 15 (hISG15) was probed with isothermal calorimetry, which suggests that the C-terminal domain of hISG15 is principally responsible for interactions. Subsequently, the structure of MERS-CoV PLpro was solved to 2.4 Å in complex with the C-terminal domain of hISG15. Utilizing this structural information, mutants were generated that lacked appreciable deISGylase activity but retained wild-type deubiquitinase and peptide cleavage activities. Hence, this provides a new platform for understanding viral deISGylase activity within MERS-CoV and other CoVs. IMPORTANCE Coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV), encode a papain-like protease (PLpro) that possesses the ability to antagonize interferon immune pathways through the removal of ubiquitin and interferon-stimulated gene product 15 (ISG15) from target proteins. The lack of CoV proteases with attenuated deISGylase activity has been a key obstacle in delineating the impact between deubiquitinase and deISGylase activities on viral host evasion and pathogenesis. Here, biophysical techniques revealed that MERS-CoV PLpro chiefly engages human ISG15 through its C-terminal domain. The first structure of MERS-CoV PLpro in complex with this domain exposed the interface between these two entities. Employing these structural insights, mutations were employed to selectively remove deISGylase activity with no appreciable impact on its other deubiquitinase and peptide cleavage biochemical properties. Excitingly, this study introduces a new tool to probe the pathogenesis of MERS-CoV and related viruses through the removal of viral deISGylase activity.

scholarly journals The 1H, 15N, and 13C resonance assignments of the N-terminal domain of the nucleocapsid protein from the Middle East respiratory syndrome coronavirus

2021 ◽  
Author(s):  
Talita Stelling de Araujo ◽  
Glauce Moreno Barbosa ◽  
Karoline Sanches ◽  
Jéssica M. Azevedo ◽  
Katia Maria dos Santos Cabral ◽  
...  
Keyword(s):  
Middle East ◽  
Nucleocapsid Protein ◽  
Resonance Assignments ◽  
Middle East Respiratory Syndrome ◽  
Terminal Domain

scholarly journals Structure of interferon-stimulated gene product 15 (ISG15) from the bat species Myotis davidii and the impact of interdomain ISG15 interactions on viral protein engagement

2019 ◽  
Vol 75 (1) ◽  
pp. 21-31 ◽  
Author(s):  
Caroline Langley ◽  
Octavia Goodwin ◽  
John V. Dzimianski ◽  
Courtney M. Daczkowski ◽  
Scott D. Pegan
Keyword(s):  
Gene Product ◽  
Species Differences ◽  
Viral Proteins ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Host Proteins ◽  
Post Translational Modifications ◽  
Interferon Responses ◽  
The Impact

Bats have long been observed to be the hosts and the origin of numerous human diseases. Bats, like all mammals, rely on a number of innate immune mechanisms to combat invading pathogens, including the interferon type I, II and III responses. Ubiquitin-like interferon-stimulated gene product 15 (ISG15) is a key modulator of these interferon responses. Within these pathways, ISG15 can serve to stabilize host proteins modulating innate immune responses and act as a cytokine. Post-translational modifications of viral proteins introduced by ISG15 have also been observed to directly affect the function of numerous viral proteins. Unlike ubiquitin, which is virtually identical across all animals, comparison of ISG15s across species reveals that they are relatively divergent, with sequence identity dropping to as low as ∼58% among mammals. In addition to serving as an obstacle to the zoonotic transmission of influenza, these ISG15 species–species differences have also long been shown to have an impact on the function of viral deISGylases. Recently, the structure of the first nonhuman ISG15, originating from mouse, suggested that the structures of human ISG15 may not be reflective of other species. Here, the structure of ISG15 from the bat species Myotis davidii solved to 1.37 Å resolution is reported. Comparison of this ISG15 structure with those from human and mouse not only underscores the structural impact of ISG15 species–species differences, but also highlights a conserved hydrophobic motif formed between the two domains of ISG15. Using the papain-like deISGylase from Severe acute respiratory syndrome coronavirus as a probe, the biochemical importance of this motif in ISG15–protein engagements was illuminated.

scholarly journals Effects of Middle East Respiratory Syndrome Coronavirus on post-traumatic stress disorder and burnout among registered nurses in South Korea

2018 ◽  
Vol 4 (2) ◽  
pp. 27 ◽  
Author(s):  
Younglee Kim ◽  
Eunju Seo ◽  
Youngseon Seo ◽  
Vivien Dee ◽  
Eunhee Hong
Keyword(s):  
Middle East ◽  
Registered Nurses ◽  
Post Traumatic Stress Disorder ◽  
Traumatic Stress ◽  
Stress Disorder ◽  
Maslach Burnout Inventory ◽  
Middle East Respiratory Syndrome ◽  
Post Traumatic Stress ◽  
Post Traumatic ◽  
The Impact

Background: The unprecedented nationwide outbreak of the Middle East Respiratory Syndrome Coronavarius (MERS-CoV) from June to July in 2015 took the Korean healthcare system unexpectedly and created physical and psychological stress and trauma to Registered Nurses unprepared to deal with the viral outbreak.Purpose: We investigated the effects of Middle East Respiratory Syndrome Coronavirus (MERS-CoV), post-traumatic stress disorder (PTSD) and burnout among Korean registered nurses (RNs).Methods: A descriptive cross sectional design using a self-administered survey of a convenience sample of 112 Korean RNs. The Impact of Event Scale-Revised-Korean version (IES-R-K) for PTSD and the Maslach Burnout Inventory-Human Services Survey (MBI-HSS) for burnout were utilized.Results: Overall prevalence for symptoms of PTSD was 50.0%. PTSD was significantly correlated to burnout (r = .480, p = .000), especially two burnout subscales, emotional exhaustion (r = .533, p = .000), and depersonalization (r = .497, p = .000).Conclusions: Future anticipatory guidance and management of traumatic outbreak or disaster should be considered for nurses’ mental health. Public health and safety at the national level must address quality health outcomes for both patients and healthcare professionals alike.

scholarly journals Biochemical and Structural Insights into the Preference of Nairoviral DeISGylases for Interferon-Stimulated Gene Product 15 Originating from Certain Species

2016 ◽  
Vol 90 (18) ◽  
pp. 8314-8327 ◽  
Author(s):  
M. K. Deaton ◽  
J. V. Dzimianski ◽  
C. M. Daczkowski ◽  
G. K. Whitney ◽  
N. J. Mank ◽  
...  
Keyword(s):  
Amino Acids ◽  
Gene Product ◽  
Posttranslational Modification ◽  
Ovarian Tumor ◽  
Mammalian Species ◽  
Amino Acid Sequences ◽  
Effector Proteins ◽  
Titration Calorimetry ◽  
Type I ◽  
The Impact

ABSTRACTThe regulation of the interferon type I (IFN-I) response has been shown to rely on posttranslational modification by ubiquitin (Ub) and Ub-like interferon-stimulated gene product 15 (ISG15) to stabilize, or activate, a variety of IFN-I signaling and downstream effector proteins. Unlike Ub, which is almost perfectly conserved among eukaryotes, ISG15 is highly divergent, even among mammals. Since zoonotic viruses rely on viral proteins to recognize, or cleave, ISG15 conjugates in order to evade, or suppress, innate immunity, the impact of ISG15 biodiversity on deISGylating proteases of the ovarian tumor family (vOTU) from nairoviruses was evaluated. The enzymatic activities of vOTUs originating from the Crimean-Congo hemorrhagic fever virus, Erve virus, and Nairobi sheep disease virus were tested against ISG15s from humans, mice, shrews, sheep, bats, and camels, which are mammalian species known to be infected by nairoviruses. This along with investigation of binding by isothermal titration calorimetry illustrated significant differences in the abilities of nairovirus deISGylases to accommodate certain species of ISG15. To investigate the molecular underpinnings of species preferences of these vOTUs, a structure was determined to 2.5 Å for a complex of Erve virus vOTU protease and a mouse ISG15 domain. This structure revealed the molecular basis of Erve virus vOTU's preference for ISG15 over Ub and the first structural insight into a nonhuman ISG15. This structure also revealed key interactions, or lack thereof, surrounding three amino acids that may drive a viral deISgylase to prefer an ISG15 from one species over that of another.IMPORTANCEViral ovarian tumor domain proteases (vOTUs) are one of the two principal classes of viral proteases observed to reverse posttranslational modification of host proteins by ubiquitin and interferon-stimulated gene product 15 (ISG15), subsequently facilitating downregulation of IFN-I signaling pathways. Unlike the case with ubiquitin, the amino acid sequences of ISG15s from various species are notably divergent. We illustrate that vOTUs have clear preferences for ISG15s from certain species. In addition, these observations are related to the molecular insights acquired via the first X-ray structure of the vOTU from the Erve nairovirus in complex with the first structurally resolved nonhuman ISG15. This information implicates certain amino acids that drive the preference of vOTUs for ISG15s from certain species.

scholarly journals SARS-CoV-2 Infection in Children; What Do We Know So Far?

2020 ◽  
pp. 76-85
Author(s):  
Benhur Şirvan Çetin
Keyword(s):  
Middle East ◽  
Child Health ◽  
Severe Acute Respiratory Syndrome ◽  
Infectious Complications ◽  
Middle East Respiratory Syndrome ◽  
Radiological Findings ◽  
The Past ◽  
The Family ◽  
The Impact ◽  
Post Infectious

After Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), SARS-CoV-2 is the newest member of the family of coronaviruses that are pathogenic to humans. The disease which occurs with SARS-CoV-2 is called coronavirus disease 2019 (COVID-19). COVID-19 was first described in December 2019 and has caused millions of people to get sick and hundreds of thousands of deaths over the past year. In this review, the epidemiology, diagnosis, clinical and aboratory features, radiological findings, treatment, and management of the disease are all reviewed from a pediatrician’s perspective. Post-infectious complications, the impact of COVID-19 on global child health, and vaccine developments were also discussed in this review.

scholarly journals Middle East Respiratory Syndrome Coronavirus Accessory Protein 4a Is a Type I Interferon Antagonist

2013 ◽  
Vol 87 (22) ◽  
pp. 12489-12495 ◽  
Author(s):  
D. Niemeyer ◽  
T. Zillinger ◽  
D. Muth ◽  
F. Zielecki ◽  
G. Horvath ◽  
...  
Keyword(s):  
Middle East ◽  
Type I Interferon ◽  
Middle East Respiratory Syndrome ◽  
Accessory Protein ◽  
Type I
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