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Scott D Pegan - One of the best experts on this subject based on the ideXlab platform.
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determining the molecular drivers of species specific interferon stimulated Gene product 15 interactions with nairovirus ovarian tumor domain proteases
PLOS ONE, 2019Co-Authors: J.v. Dzimianski, Eric Bergeron, Florine E M Scholte, Isabelle L Williams, Caroline Langley, Brendan T Freitas, Jessica R Spengler, Scott D PeganAbstract:Tick-borne nairoviruses (order Bunyavirales) encode an ovarian tumor domain protease (OTU) that suppresses the innate immune response by reversing the post-translational modification of proteins by ubiquitin (Ub) and Interferon-Stimulated Gene product 15 (ISG15). Ub is highly conserved across eukaryotes, whereas ISG15 is only present in vertebrates and shows substantial sequence diversity. Prior attempts to address the effect of ISG15 diversity on viral protein-ISG15 interactions have focused on only a single species' ISG15 or a limited selection of nairovirus OTUs. To gain a more complete perspective of OTU-ISG15 interactions, we biochemically assessed the relative activities of 14 diverse nairovirus OTUs for 12 species' ISG15 and found that ISG15 activity is predominantly restricted to particular nairovirus lineages reflecting, in General, known virus-host associations. To uncover the underlying molecular factors driving OTUs affinity for ISG15, X-ray crystal structures of Kupe virus and Ganjam virus OTUs bound to sheep ISG15 were solved and compared to complexes of Crimean-Congo hemorrhagic fever virus and Erve virus OTUs bound to human and mouse ISG15, respectively. Through mutational and structural analysis seven residues in ISG15 were identified that predominantly influence ISG15 species specificity among nairovirus OTUs. Additionally, OTU residues were identified that influence ISG15 preference, suggesting the potential for viral OTUs to adapt to different host ISG15s. These findings provide a foundation to further develop research methods to trace nairovirus-host relationships and delineate the full impact of ISG15 diversity on nairovirus infection.
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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
Acta Crystallographica Section D-biological Crystallography, 2019Co-Authors: Caroline Langley, J.v. Dzimianski, Octavia Y Goodwin, C M Daczkowski, Scott D PeganAbstract: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 A 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.
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crimean congo hemorrhagic fever virus suppresses innate immune responses via a ubiquitin and isg15 specific protease
Cell Reports, 2017Co-Authors: Florine E M Scholte, J.v. Dzimianski, Christina F. Spiropoulou, Scott D Pegan, Stuart T. Nichol, Jessica R Spengler, Marko Zivcec, Michelle K Deaton, Stephen R Welch, Eric BergeronAbstract:Antiviral responses are regulated by conjugation of ubiquitin (Ub) and Interferon-Stimulated Gene 15 (ISG15) to proteins. Certain classes of viruses encode Ub- or ISG15-specific proteases belonging to the ovarian tumor (OTU) superfamily. Their activity is thought to suppress cellular immune responses, but studies demonstrating the function of viral OTU proteases during infection are lacking. Crimean-Congo hemorrhagic fever virus (CCHFV, family Nairoviridae) is a highly pathogenic human virus that encodes an OTU with both deubiquitinase and deISGylase activity as part of the viral RNA polymerase. We investigated CCHFV OTU function by inactivating protease catalytic activity or by selectively disrupting its deubiquitinase and deISGylase activity using reverse Genetics. CCHFV OTU inactivation blocked viral replication independently of its RNA polymerase activity, while deubiquitinase activity proved critical for suppressing the interferon responses. Our findings provide insights into viral OTU functions and support the development of therapeutics and vaccines.
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Structural Insights into the Interaction of Coronavirus Papain-Like Proteases and Interferon-Stimulated Gene Product 15 from Different Species.
Journal of Molecular Biology, 2017Co-Authors: Courtney M. Daczkowski, J.v. Dzimianski, Jozlyn R. Clasman, O.y. Goodwin, Andrew D Mesecar, Scott D PeganAbstract:Abstract Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) encode multifunctional papain-like proteases (PLPs) that have the ability to process the viral polyprotein to facilitate RNA replication and antagonize the host innate immune response. The latter function involves reversing the post-translational modification of cellular proteins conjugated with either ubiquitin (Ub) or Ub-like Interferon-Stimulated Gene product 15 (ISG15). Ub is known to be highly conserved among eukaryotes, but surprisingly, ISG15 is highly divergent among animals. The ramifications of this sequence divergence to the recognition of ISG15 by coronavirus PLPs at a structural and biochemical level are poorly understood. Therefore, the activity of PLPs from SARS-CoV, MERS‐CoV, and mouse hepatitis virus was evaluated against seven ISG15s originating from an assortment of animal species susceptible, and not, to certain coronavirus infections. Excitingly, our kinetic, thermodynamic, and structural analysis revealed an array of different preferences among PLPs. Included in these studies is the first insight into a coronavirus PLP’s interface with ISG15 via SARS-CoV PLpro in complex with the principle binding domain of human ISG15 (hISG15) and mouse ISG15s (mISG15s). The first X-ray structure of the full-length mISG15 protein is also reported and highlights a unique, twisted hinge region of ISG15 that is not conserved in hISG15, suggesting a potential role in differential recognition. Taken together, this new information provides a structural and biochemical understanding of the distinct specificities among coronavirus PLPs observed and addresses a critical gap of how PLPs can interact with ISG15s from a wide variety of species.
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the votu domain of highly pathogenic porcine reproductive and respiratory syndrome virus displays a differential substrate preference
Virology, 2014Co-Authors: Michelle K Deaton, Allyn Spear, Kay S Faaberg, Scott D PeganAbstract:Arterivirus genus member Porcine reproductive and respiratory syndrome virus (PRRSV) causes an economically devastating disease, recently exacerbated by the emergence of highly pathogenic strains (HP-PRRSV). Within the nonstructural protein 2 of PRRSV is a deubiquitinating enzyme domain belonging to the viral ovarian tumor (vOTU) protease superfamily. vOTUs, which can greatly vary in their preference for their host ubiquitin (Ub) and Ub-like substrates such as interferon stimulated Gene 15 (ISG15), have been implicated as a potential virulence factor. Since various strains of PRRSV have large variations in virulence, the specificity of vOTUs from two PRRSV strains of varying virulence were determined. While both vOTUs showed de-ubiquitinating activity and markedly low deISGylating activity, HP-PRRSV demonstrated a strong preference for lysine 63-linked poly-Ubiquitin, tied to innate immune response regulation. This represents the first report of biochemical activity unique to HP-PRRSV that has implications for a potential increase in immunosuppression and virulence.
Steven A Greenberg - One of the best experts on this subject based on the ideXlab platform.
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type 1 interferons inhibit myotube formation independently of upregulation of interferon stimulated Gene 15
PLOS ONE, 2013Co-Authors: Sara Franzi, Remedios Nazareno, Steven A Greenberg, Mohammad SalajeghehAbstract:INTRODUCTION: Type 1 interferon (IFN)-inducible Genes and their inducible products are upregulated in dermatomyositis muscle. Of these, IFN-stimulated Gene 15 (ISG15) is one of the most upregulated, suggesting its possible involvement in the pathoGenesis of this disease. To test this postulate, we developed a model of type 1 IFN mediated myotube toxicity and assessed whether or not downregulation of ISG15 expression prevents this toxicity. METHODS: Mouse myoblasts (C2C12 cell line) were cultured in the presence of type 1 or type 2 IFNs and ISG15 expression assessed by microarray analysis. The morphology of newly formed myotubes was assessed by measuring their length, diameter, and area on micrographs using imaging software. ISG15 expression was silenced through transfection with small interference RNA. RESULTS: Type 1 IFNs, especially IFN-beta, increased ISG15 expression in C2C12 cells and impaired myotube formation. Silencing of ISG15 resulted in knockdown of ISG15 protein, but without phenotypic rescue of myotube formation. DISCUSSION: IFN-beta affects myoblast differentiation ability and myotube morphology in vitro.These studies provide evidence that ISG15, which is highly upregulated in dermatomyositis muscle, does not appear to play a key role in IFN-beta-mediated C2C12 myoblast cell fusion.
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type 1 interferons inhibit myotube formation independently of upregulation of interferon stimulated Gene 15
PLOS ONE, 2013Co-Authors: Sara Franzi, Remedios Nazareno, Steven A Greenberg, Mohammad SalajeghehAbstract:Introduction Type 1 interferon (IFN)-inducible Genes and their inducible products are upregulated in dermatomyositis muscle. Of these, IFN-stimulated Gene 15 (ISG15) is one of the most upregulated, suggesting its possible involvement in the pathoGenesis of this disease. To test this postulate, we developed a model of type 1 IFN mediated myotube toxicity and assessed whether or not downregulation of ISG15 expression prevents this toxicity.
Mohammad Salajegheh - One of the best experts on this subject based on the ideXlab platform.
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type 1 interferons inhibit myotube formation independently of upregulation of interferon stimulated Gene 15
PLOS ONE, 2013Co-Authors: Sara Franzi, Remedios Nazareno, Steven A Greenberg, Mohammad SalajeghehAbstract:INTRODUCTION: Type 1 interferon (IFN)-inducible Genes and their inducible products are upregulated in dermatomyositis muscle. Of these, IFN-stimulated Gene 15 (ISG15) is one of the most upregulated, suggesting its possible involvement in the pathoGenesis of this disease. To test this postulate, we developed a model of type 1 IFN mediated myotube toxicity and assessed whether or not downregulation of ISG15 expression prevents this toxicity. METHODS: Mouse myoblasts (C2C12 cell line) were cultured in the presence of type 1 or type 2 IFNs and ISG15 expression assessed by microarray analysis. The morphology of newly formed myotubes was assessed by measuring their length, diameter, and area on micrographs using imaging software. ISG15 expression was silenced through transfection with small interference RNA. RESULTS: Type 1 IFNs, especially IFN-beta, increased ISG15 expression in C2C12 cells and impaired myotube formation. Silencing of ISG15 resulted in knockdown of ISG15 protein, but without phenotypic rescue of myotube formation. DISCUSSION: IFN-beta affects myoblast differentiation ability and myotube morphology in vitro.These studies provide evidence that ISG15, which is highly upregulated in dermatomyositis muscle, does not appear to play a key role in IFN-beta-mediated C2C12 myoblast cell fusion.
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type 1 interferons inhibit myotube formation independently of upregulation of interferon stimulated Gene 15
PLOS ONE, 2013Co-Authors: Sara Franzi, Remedios Nazareno, Steven A Greenberg, Mohammad SalajeghehAbstract:Introduction Type 1 interferon (IFN)-inducible Genes and their inducible products are upregulated in dermatomyositis muscle. Of these, IFN-stimulated Gene 15 (ISG15) is one of the most upregulated, suggesting its possible involvement in the pathoGenesis of this disease. To test this postulate, we developed a model of type 1 IFN mediated myotube toxicity and assessed whether or not downregulation of ISG15 expression prevents this toxicity.
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interferon stimulated Gene 15 isg15 conjugates proteins in dermatomyositis muscle with perifascicular atrophy
Annals of Neurology, 2010Co-Authors: Mohammad Salajegheh, Ronan J Walsh, Anne Liao, Bryan Krastins, Sek Won Kong, Jack L Pinkus, Remedios Nazareno, Chris Morehouse, A Amato, Brandon W HiggsAbstract:Dermatomyositis (DM) is an autoimmune disease of unknown cause primarily affecting skeletal muscle and skin. The characteristic muscle pathology of DM is notable for capillary abnormalities and small, abnormal appearing muscle fibers around the periphery of some muscle fascicles bordering the perimysial connective tissue, a lesion called perifascicular atrophy (PFA). Recent microarray and pathological studies have pointed towards a mechanism of tissue injury in DM associated with the overexpression of type 1 interferon-inducible Genes. Over 85% of the highest expressed transcripts in muscle from DM compared to normal and other inflammatory myopathies are from Genes known to be induced by type 1 interferons.1 Plasmacytoid dendritic cells (pDCs), cells that produce high levels of type 1 interferons, have infiltrated DM muscle1 and skin.2 Expression of the type 1 interferon-inducible protein MxA occurs in the characteristic sites of DM pathology, the perifascicular myofibers and capillaries. These findings suggest that injury to capillaries and myofibers may result directly from the intracellular overproduction of one or more type 1 interferon-inducible transcripts or proteins. Interferon-Stimulated Gene 15 (ISG15), a type 1 interferon-inducible protein, is an ubiquitin-like modifier with poorly understood function. The enzymatic pathway for ISG15 conjugation to a target protein involves three conjugating enzymes, the E1 Ube1L,3 the E2 Ube2L6,4 and the E3 HERC5,5, 6 and a deconjugating enzyme USP18.7 Immunoprecipitates of ISG15 from interferon-β stimulated HeLa cells contain many putative ISG15-conjugated proteins.8 The conjugation of ISG15 to proteins in a human tissue sample has only been reported in 3 endometrial and 2 colon cancer biopsy specimens;9 the identities of any such proteins are unknown. We previously reported that ISG15 is the single most overexpressed Gene in DM muscle compared to both normal muscle and muscle from patients with other inflammatory myopathies.1 It is also highly expressed in circulating mononuclear blood cells of patients with DM.10 In this study, we have examined the ISG15 pathway in DM and other inflammatory myopathy muscle biopsy specimens and in cultured human skeletal muscle exposed to type 1 interferons.
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interferon stimulated Gene 15 isg15 conjugates proteins in dermatomyositis muscle with perifascicular atrophy
Annals of Neurology, 2010Co-Authors: Mohammad Salajegheh, Ronan J Walsh, Anne Liao, Bryan Krastins, Sek Won Kong, Jack L Pinkus, Remedios Nazareno, Chris Morehouse, A Amato, Brandon W HiggsAbstract:Dermatomyositis (DM) is an autoimmune disease of unknown cause primarily affecting skeletal muscle and skin. The characteristic muscle pathology of DM is notable for capillary abnormalities and small, abnormal appearing muscle fibers around the periphery of some muscle fascicles bordering the perimysial connective tissue, a lesion called perifascicular atrophy (PFA). Recent microarray and pathological studies have pointed towards a mechanism of tissue injury in DM associated with the overexpression of type 1 interferon-inducible Genes. Over 85% of the highest expressed transcripts in muscle from DM compared to normal and other inflammatory myopathies are from Genes known to be induced by type 1 interferons.1 Plasmacytoid dendritic cells (pDCs), cells that produce high levels of type 1 interferons, have infiltrated DM muscle1 and skin.2 Expression of the type 1 interferon-inducible protein MxA occurs in the characteristic sites of DM pathology, the perifascicular myofibers and capillaries. These findings suggest that injury to capillaries and myofibers may result directly from the intracellular overproduction of one or more type 1 interferon-inducible transcripts or proteins. Interferon-Stimulated Gene 15 (ISG15), a type 1 interferon-inducible protein, is an ubiquitin-like modifier with poorly understood function. The enzymatic pathway for ISG15 conjugation to a target protein involves three conjugating enzymes, the E1 Ube1L,3 the E2 Ube2L6,4 and the E3 HERC5,5, 6 and a deconjugating enzyme USP18.7 Immunoprecipitates of ISG15 from interferon-β stimulated HeLa cells contain many putative ISG15-conjugated proteins.8 The conjugation of ISG15 to proteins in a human tissue sample has only been reported in 3 endometrial and 2 colon cancer biopsy specimens;9 the identities of any such proteins are unknown. We previously reported that ISG15 is the single most overexpressed Gene in DM muscle compared to both normal muscle and muscle from patients with other inflammatory myopathies.1 It is also highly expressed in circulating mononuclear blood cells of patients with DM.10 In this study, we have examined the ISG15 pathway in DM and other inflammatory myopathy muscle biopsy specimens and in cultured human skeletal muscle exposed to type 1 interferons.
J.v. Dzimianski - One of the best experts on this subject based on the ideXlab platform.
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determining the molecular drivers of species specific interferon stimulated Gene product 15 interactions with nairovirus ovarian tumor domain proteases
PLOS ONE, 2019Co-Authors: J.v. Dzimianski, Eric Bergeron, Florine E M Scholte, Isabelle L Williams, Caroline Langley, Brendan T Freitas, Jessica R Spengler, Scott D PeganAbstract:Tick-borne nairoviruses (order Bunyavirales) encode an ovarian tumor domain protease (OTU) that suppresses the innate immune response by reversing the post-translational modification of proteins by ubiquitin (Ub) and Interferon-Stimulated Gene product 15 (ISG15). Ub is highly conserved across eukaryotes, whereas ISG15 is only present in vertebrates and shows substantial sequence diversity. Prior attempts to address the effect of ISG15 diversity on viral protein-ISG15 interactions have focused on only a single species' ISG15 or a limited selection of nairovirus OTUs. To gain a more complete perspective of OTU-ISG15 interactions, we biochemically assessed the relative activities of 14 diverse nairovirus OTUs for 12 species' ISG15 and found that ISG15 activity is predominantly restricted to particular nairovirus lineages reflecting, in General, known virus-host associations. To uncover the underlying molecular factors driving OTUs affinity for ISG15, X-ray crystal structures of Kupe virus and Ganjam virus OTUs bound to sheep ISG15 were solved and compared to complexes of Crimean-Congo hemorrhagic fever virus and Erve virus OTUs bound to human and mouse ISG15, respectively. Through mutational and structural analysis seven residues in ISG15 were identified that predominantly influence ISG15 species specificity among nairovirus OTUs. Additionally, OTU residues were identified that influence ISG15 preference, suggesting the potential for viral OTUs to adapt to different host ISG15s. These findings provide a foundation to further develop research methods to trace nairovirus-host relationships and delineate the full impact of ISG15 diversity on nairovirus infection.
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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
Acta Crystallographica Section D-biological Crystallography, 2019Co-Authors: Caroline Langley, J.v. Dzimianski, Octavia Y Goodwin, C M Daczkowski, Scott D PeganAbstract: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 A 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.
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crimean congo hemorrhagic fever virus suppresses innate immune responses via a ubiquitin and isg15 specific protease
Cell Reports, 2017Co-Authors: Florine E M Scholte, J.v. Dzimianski, Christina F. Spiropoulou, Scott D Pegan, Stuart T. Nichol, Jessica R Spengler, Marko Zivcec, Michelle K Deaton, Stephen R Welch, Eric BergeronAbstract:Antiviral responses are regulated by conjugation of ubiquitin (Ub) and Interferon-Stimulated Gene 15 (ISG15) to proteins. Certain classes of viruses encode Ub- or ISG15-specific proteases belonging to the ovarian tumor (OTU) superfamily. Their activity is thought to suppress cellular immune responses, but studies demonstrating the function of viral OTU proteases during infection are lacking. Crimean-Congo hemorrhagic fever virus (CCHFV, family Nairoviridae) is a highly pathogenic human virus that encodes an OTU with both deubiquitinase and deISGylase activity as part of the viral RNA polymerase. We investigated CCHFV OTU function by inactivating protease catalytic activity or by selectively disrupting its deubiquitinase and deISGylase activity using reverse Genetics. CCHFV OTU inactivation blocked viral replication independently of its RNA polymerase activity, while deubiquitinase activity proved critical for suppressing the interferon responses. Our findings provide insights into viral OTU functions and support the development of therapeutics and vaccines.
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Structural Insights into the Interaction of Coronavirus Papain-Like Proteases and Interferon-Stimulated Gene Product 15 from Different Species.
Journal of Molecular Biology, 2017Co-Authors: Courtney M. Daczkowski, J.v. Dzimianski, Jozlyn R. Clasman, O.y. Goodwin, Andrew D Mesecar, Scott D PeganAbstract:Abstract Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) encode multifunctional papain-like proteases (PLPs) that have the ability to process the viral polyprotein to facilitate RNA replication and antagonize the host innate immune response. The latter function involves reversing the post-translational modification of cellular proteins conjugated with either ubiquitin (Ub) or Ub-like Interferon-Stimulated Gene product 15 (ISG15). Ub is known to be highly conserved among eukaryotes, but surprisingly, ISG15 is highly divergent among animals. The ramifications of this sequence divergence to the recognition of ISG15 by coronavirus PLPs at a structural and biochemical level are poorly understood. Therefore, the activity of PLPs from SARS-CoV, MERS‐CoV, and mouse hepatitis virus was evaluated against seven ISG15s originating from an assortment of animal species susceptible, and not, to certain coronavirus infections. Excitingly, our kinetic, thermodynamic, and structural analysis revealed an array of different preferences among PLPs. Included in these studies is the first insight into a coronavirus PLP’s interface with ISG15 via SARS-CoV PLpro in complex with the principle binding domain of human ISG15 (hISG15) and mouse ISG15s (mISG15s). The first X-ray structure of the full-length mISG15 protein is also reported and highlights a unique, twisted hinge region of ISG15 that is not conserved in hISG15, suggesting a potential role in differential recognition. Taken together, this new information provides a structural and biochemical understanding of the distinct specificities among coronavirus PLPs observed and addresses a critical gap of how PLPs can interact with ISG15s from a wide variety of species.
Kristen M John - One of the best experts on this subject based on the ideXlab platform.
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cigarette smoke exposure and inflammatory signaling increase the expression of the sars cov 2 receptor ace2 in the respiratory tract
Developmental Cell, 2020Co-Authors: Joan C Smith, Erin L Sausville, Vishruth Girish, Monet Lou Yuan, Anand Vasudevan, Kristen M JohnAbstract:The factors mediating fatal SARS-CoV-2 infections are poorly understood. Here, we show that cigarette smoke causes a dose-dependent upregulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, in rodent and human lungs. Using single-cell sequencing data, we demonstrate that ACE2 is expressed in a subset of secretory cells in the respiratory tract. Chronic smoke exposure triggers the expansion of this cell population and a concomitant increase in ACE2 expression. In contrast, quitting smoking decreases the abundance of these secretory cells and reduces ACE2 levels. Finally, we demonstrate that ACE2 expression is responsive to inflammatory signaling and can be upregulated by viral infections or interferon treatment. Taken together, these results may partially explain why smokers are particularly susceptible to severe SARS-CoV-2 infections. Furthermore, our work identifies ACE2 as an Interferon-Stimulated Gene in lung cells, suggesting that SARS-CoV-2 infections could create positive feedback loops that increase ACE2 levels and facilitate viral dissemination.