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Dongyan Jin - One of the best experts on this subject based on the ideXlab platform.
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Middle east respiratory syndroMe coronavirus M Protein suppresses type i interferon expression through the inhibition of tbk1 dependent phosphorylation of irf3
Emerging microbes & infections, 2016Co-Authors: Pakyin Lui, Kam-leung Siu, Patrick C Y Woo, Chiping Chan, Lokyin Roy Wong, Cheuklai Fung, Man Lung Yeung, Kitsan Yuen, Kwokyung Yuen, Dongyan JinAbstract:Middle East respiratory syndroMe coronavirus (MERS-CoV) infection has claiMed hundreds of lives and has becoMe a global threat since its eMergence in Saudi Arabia in 2012. The ability of MERS-CoV to evade the host innate antiviral response May contribute to its severe pathogenesis. Many MERS-CoV-encoded Proteins were identified to have interferon (IFN)-antagonizing properties, which correlates well with the reduced IFN levels observed in infected patients and ex vivo Models. In this study, we fully characterized the IFN-antagonizing property of the MERS-CoV M Protein. Expression of MERS-CoV M Protein suppressed type I IFN expression in response to Sendai virus infection or poly(I:C) induction. This suppressive effect was found to be specific for the activation of IFN regulatory factor 3 (IRF3) but not nuclear factor-κB. MERS-CoV M Protein interacted with TRAF3 and disrupted TRAF3–TBK1 association leading to reduced IRF3 activation. M Proteins froM MERS-CoV and SARS-CoV have three highly siMilar conserved N-terMinal transMeMbrane doMains and a C-terMinal region. Using chiMeric and truncation Mutants, the N-terMinal transMeMbrane doMains of the MERS-CoV M Protein were found to be sufficient for its inhibitory effect on IFN expression, whereas the C-terMinal doMain was unable to induce this suppression. Collectively, our findings suggest a coMMon and conserved MechanisM through which highly pathogenic MERS-CoV and SARS-CoV harness their M Proteins to suppress type I IFN expression at the level of TBK1-dependent phosphorylation and activation of IRF3 resulting in evasion of the host innate antiviral response.
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suppression of innate antiviral response by severe acute respiratory syndroMe coronavirus M Protein is Mediated through the first transMeMbrane doMain
Cellular & Molecular Immunology, 2014Co-Authors: Kam-leung Siu, Kinhang Kok, Patrick C Y Woo, Chiping Chan, Dongyan JinAbstract:Coronaviruses have developed various Measures to evade innate iMMunity. We have previously shown that severe acute respiratory syndroMe (SARS) coronavirus M Protein suppresses type I interferon (IFN) production by iMpeding the forMation of functional TRAF3-containing coMplex. In this study, we deMonstrate that the IFN-antagonizing activity is specific to SARS coronavirus M Protein and is Mediated through its first transMeMbrane doMain (TM1) located at the N terMinus. M Protein froM huMan coronavirus HKU1 does not inhibit IFN production. Whereas N-linked glycosylation of SARS coronavirus M Protein has no influence on IFN antagonisM, TM1 is indispensable for the suppression of IFN production. TM1 targets SARS coronavirus M Protein and heterologous Proteins to the Golgi apparatus, yet Golgi localization is required but not sufficient for IFN antagonisM. Mechanistically, TM1 is capable of binding with RIG-I, TRAF3, TBK1 and IKKe, and preventing the interaction of TRAF3 with its downstreaM effectors. Our work defines the Molecular architecture of SARS coronavirus M Protein required for suppression of innate antiviral response.
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severe acute respiratory syndroMe coronavirus M Protein inhibits type i interferon production by iMpeding the forMation of traf3 tank tbk1 ikkϵ coMplex
Journal of Biological Chemistry, 2009Co-Authors: Kam-leung Siu, Kinhang Kok, Ming Him James Ng, Vincent K M Poon, Bojian Zheng, Dongyan JinAbstract:Severe acute respiratory syndroMe (SARS) coronavirus is highly pathogenic in huMans and evades innate iMMunity at Multiple levels. It has evolved various strategies to counteract the production and action of type I interferons, which Mobilize the front-line defense against viral infection. In this study we deMonstrate that SARS coronavirus M Protein inhibits gene transcription of type I interferons. M Protein potently antagonizes the activation of interferon-stiMulated response eleMent-dependent transcription by double-stranded RNA, RIG-I, MDA5, TBK1, IKKϵ, and virus-induced signaling adaptor (VISA) but has no influence on the transcriptional activity of this eleMent when IRF3 or IRF7 is overexpressed. M Protein physically associates with RIG-I, TBK1, IKKϵ, and TRAF3 and likely sequesters soMe of theM in MeMbrane-associated cytoplasMic coMpartMents. Consequently, the expression of M Protein prevents the forMation of TRAF3·TANK·TBK1/IKKϵ coMplex and thereby inhibits TBK1/IKKϵ-dependent activation of IRF3/IRF7 transcription factors. Taken together, our findings reveal a new MechanisM by which SARS coronavirus circuMvents the production of type I interferons.
Kevin D Corbett - One of the best experts on this subject based on the ideXlab platform.
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the sars cov 2 nucleocapsid phosphoProtein forMs Mutually exclusive condensates with rna and the MeMbrane associated M Protein
Nature Communications, 2021Co-Authors: Digvijay Singh, Elizabeth Villa, Don W Cleveland, Yong Cao, Jolene K Diedrich, John R Yates, Kevin D CorbettAbstract:The Multifunctional nucleocapsid (N) Protein in SARS-CoV-2 binds the ~30 kb viral RNA genoMe to aid its packaging into the 80-90 nM MeMbrane-enveloped virion. The N Protein is coMposed of N-terMinal RNA-binding and C-terMinal diMerization doMains that are flanked by three intrinsically disordered regions. Here we deMonstrate that the N Protein's central disordered doMain drives phase separation with RNA, and that phosphorylation of an adjacent serine/arginine rich region Modulates the physical properties of the resulting condensates. In cells, N forMs condensates that recruit the stress granule Protein G3BP1, highlighting a potential role for N in G3BP1 sequestration and stress granule inhibition. The SARS-CoV-2 MeMbrane (M) Protein independently induces N Protein phase separation, and three-coMponent Mixtures of N + M + RNA forM condensates with Mutually exclusive coMpartMents containing N + M or N + RNA, including annular structures in which the M Protein coats the outside of an N + RNA condensate. These findings support a Model in which phase separation of the SARS-CoV-2 N Protein contributes both to suppression of the G3BP1-dependent host iMMune response and to packaging genoMic RNA during virion asseMbly.
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the sars cov 2 nucleocapsid phosphoProtein forMs Mutually exclusive condensates with rna and the MeMbrane associated M Protein
bioRxiv, 2020Co-Authors: Digvijay Singh, Elizabeth Villa, Don W Cleveland, Kevin D CorbettAbstract:The Multifunctional nucleocapsid (N) Protein in SARS-CoV-2 binds the ~30 kb viral RNA genoMe to aid its packaging into the 80-90nM MeMbrane-enveloped virion. The N Protein is coMposed of N-terMinal RNA-binding and C-terMinal diMerization doMains that are flanked by three intrinsically disordered regions. Here we deMonstrate that a centrally located 40 aMino acid intrinsically disordered doMain drives phase separation of N Protein when bound to RNA, with the Morphology of the resulting condensates affected by inclusion in the RNA of the putative SARS-CoV-2 packaging signal. The SARS-CoV-2 M Protein, norMally eMbedded in the virion MeMbrane with its C-terMinus extending into the virion core, independently induces N Protein phase separation that is dependent on the N Protein's C-terMinal diMerization doMain and disordered region. Three-coMponent Mixtures of N+M+RNA forM condensates with Mutually exclusive coMpartMents containing N+M or N+RNA, including spherical annular structures in which the M Protein coats the outside of an N+RNA condensate. These findings support a Model in which phase separation of the N Protein with both the viral genoMic RNA and the SARS-CoV-2 M Protein facilitates RNA packaging and virion asseMbly.
Kam-leung Siu - One of the best experts on this subject based on the ideXlab platform.
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Middle east respiratory syndroMe coronavirus M Protein suppresses type i interferon expression through the inhibition of tbk1 dependent phosphorylation of irf3
Emerging microbes & infections, 2016Co-Authors: Pakyin Lui, Kam-leung Siu, Patrick C Y Woo, Chiping Chan, Lokyin Roy Wong, Cheuklai Fung, Man Lung Yeung, Kitsan Yuen, Kwokyung Yuen, Dongyan JinAbstract:Middle East respiratory syndroMe coronavirus (MERS-CoV) infection has claiMed hundreds of lives and has becoMe a global threat since its eMergence in Saudi Arabia in 2012. The ability of MERS-CoV to evade the host innate antiviral response May contribute to its severe pathogenesis. Many MERS-CoV-encoded Proteins were identified to have interferon (IFN)-antagonizing properties, which correlates well with the reduced IFN levels observed in infected patients and ex vivo Models. In this study, we fully characterized the IFN-antagonizing property of the MERS-CoV M Protein. Expression of MERS-CoV M Protein suppressed type I IFN expression in response to Sendai virus infection or poly(I:C) induction. This suppressive effect was found to be specific for the activation of IFN regulatory factor 3 (IRF3) but not nuclear factor-κB. MERS-CoV M Protein interacted with TRAF3 and disrupted TRAF3–TBK1 association leading to reduced IRF3 activation. M Proteins froM MERS-CoV and SARS-CoV have three highly siMilar conserved N-terMinal transMeMbrane doMains and a C-terMinal region. Using chiMeric and truncation Mutants, the N-terMinal transMeMbrane doMains of the MERS-CoV M Protein were found to be sufficient for its inhibitory effect on IFN expression, whereas the C-terMinal doMain was unable to induce this suppression. Collectively, our findings suggest a coMMon and conserved MechanisM through which highly pathogenic MERS-CoV and SARS-CoV harness their M Proteins to suppress type I IFN expression at the level of TBK1-dependent phosphorylation and activation of IRF3 resulting in evasion of the host innate antiviral response.
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suppression of innate antiviral response by severe acute respiratory syndroMe coronavirus M Protein is Mediated through the first transMeMbrane doMain
Cellular & Molecular Immunology, 2014Co-Authors: Kam-leung Siu, Kinhang Kok, Patrick C Y Woo, Chiping Chan, Dongyan JinAbstract:Coronaviruses have developed various Measures to evade innate iMMunity. We have previously shown that severe acute respiratory syndroMe (SARS) coronavirus M Protein suppresses type I interferon (IFN) production by iMpeding the forMation of functional TRAF3-containing coMplex. In this study, we deMonstrate that the IFN-antagonizing activity is specific to SARS coronavirus M Protein and is Mediated through its first transMeMbrane doMain (TM1) located at the N terMinus. M Protein froM huMan coronavirus HKU1 does not inhibit IFN production. Whereas N-linked glycosylation of SARS coronavirus M Protein has no influence on IFN antagonisM, TM1 is indispensable for the suppression of IFN production. TM1 targets SARS coronavirus M Protein and heterologous Proteins to the Golgi apparatus, yet Golgi localization is required but not sufficient for IFN antagonisM. Mechanistically, TM1 is capable of binding with RIG-I, TRAF3, TBK1 and IKKe, and preventing the interaction of TRAF3 with its downstreaM effectors. Our work defines the Molecular architecture of SARS coronavirus M Protein required for suppression of innate antiviral response.
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severe acute respiratory syndroMe coronavirus M Protein inhibits type i interferon production by iMpeding the forMation of traf3 tank tbk1 ikkϵ coMplex
Journal of Biological Chemistry, 2009Co-Authors: Kam-leung Siu, Kinhang Kok, Ming Him James Ng, Vincent K M Poon, Bojian Zheng, Dongyan JinAbstract:Severe acute respiratory syndroMe (SARS) coronavirus is highly pathogenic in huMans and evades innate iMMunity at Multiple levels. It has evolved various strategies to counteract the production and action of type I interferons, which Mobilize the front-line defense against viral infection. In this study we deMonstrate that SARS coronavirus M Protein inhibits gene transcription of type I interferons. M Protein potently antagonizes the activation of interferon-stiMulated response eleMent-dependent transcription by double-stranded RNA, RIG-I, MDA5, TBK1, IKKϵ, and virus-induced signaling adaptor (VISA) but has no influence on the transcriptional activity of this eleMent when IRF3 or IRF7 is overexpressed. M Protein physically associates with RIG-I, TBK1, IKKϵ, and TRAF3 and likely sequesters soMe of theM in MeMbrane-associated cytoplasMic coMpartMents. Consequently, the expression of M Protein prevents the forMation of TRAF3·TANK·TBK1/IKKϵ coMplex and thereby inhibits TBK1/IKKϵ-dependent activation of IRF3/IRF7 transcription factors. Taken together, our findings reveal a new MechanisM by which SARS coronavirus circuMvents the production of type I interferons.
David L. Gordon - One of the best experts on this subject based on the ideXlab platform.
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a coMMon site within factor h scr 7 responsible for binding heparin c reactive Protein and streptococcal M Protein
European Journal of Immunology, 2003Co-Authors: Eleni Giannakis, Rebecca J. Ormsby, Vince A. Fischetti, Sakari T Jokiranta, D A Male, Shoba Ranganathan, Carolyn Mold, David L. GordonAbstract:The coMpleMent inhibitor factor H (fH) interacts via its seventh short consensus repeat (SCR) doMain with Multiple ligands including heparin, streptococcal M Protein and C-reactive Protein (CRP). The aiM of this study was to localize the residues in SCR 7 required for these interactions. We initially built a hoMology Model of fH SCR 6–7 using the averaged NMR structures of fH SCR 15–16 and vaccinia control Protein SCR 3–4 as teMplates. Electrostatic potentials of the Model's surface deMonstrated a co-localization of three clusters of positively charged residues on SCR 7, labeled site A (R369 and K370), site B (R386 and K387) and site C (K392). These residues, localized to the linker region preceding SCR 7 and to the end of a "hypervariable loop" in SCR 7, were systeMatically replaced with uncharged alanine residues in an fH construct containing SCR 1–7. The resulting Proteins were expressed in the Methylotrophic yeast, Pichia pastoris. By ELISA analysis we deMonstrated: first, that substituting site A inhibited heparin and CRP binding; secondly, that substituting site B inhibited binding to heparin, CRP and M Protein; and thirdly, that substituting site C clearly inhibited only heparin binding.
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a coMMon site within factor h scr 7 responsible for binding heparin c reactive Protein and streptococcal M Protein
European Journal of Immunology, 2003Co-Authors: E Giannakis, Rebecca J. Ormsby, Vince A. Fischetti, Sakari T Jokiranta, D A Male, Shoba Ranganathan, Carolyn Mold, David L. GordonAbstract:The coMpleMent inhibitor factor H (fH) interacts via its seventh short consensus repeat (SCR) doMain with Multiple ligands including heparin, streptococcal M Protein and C-reactive Protein (CRP). The aiM of this study was to localize the residues in SCR 7 required for these interactions. We initially built a hoMology Model of fH SCR 6–7 using the averaged NMR structures of fH SCR 15–16 and vaccinia control Protein SCR 3–4 as teMplates. Electrostatic potentials of the Model's surface deMonstrated a co-localization of three clusters of positively charged residues on SCR 7, labeled site A (R369 and K370), site B (R386 and K387) and site C (K392). These residues, localized to the linker region preceding SCR 7 and to the end of a "hypervariable loop" in SCR 7, were systeMatically replaced with uncharged alanine residues in an fH construct containing SCR 1–7. The resulting Proteins were expressed in the Methylotrophic yeast, Pichia pastoris. By ELISA analysis we deMonstrated: first, that substituting site A inhibited heparin and CRP binding; secondly, that substituting site B inhibited binding to heparin, CRP and M Protein; and thirdly, that substituting site C clearly inhibited only heparin binding.
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Identification of the Streptococcal M Protein Binding Site on MeMbrane Cofactor Protein (CD46)
Journal of immunology (Baltimore Md. : 1950), 2002Co-Authors: Eleni Giannakis, Dale Christiansen, Bruce E. Loveland, T. Sakari Jokiranta, Rebecca J. Ormsby, Thomas G. Duthy, Dean A. Male, Vince A. Fischetti, Christopher J. Bagley, David L. GordonAbstract:Adherence of group A streptococcus (GAS) to keratinocytes is Mediated by an interaction between huMan CD46 (MeMbrane cofactor Protein) with streptococcal cell surface M Protein. CD46 belongs to a faMily of Proteins that contain structurally related short consensus repeat (SCR) doMains and regulate the activation of the coMpleMent coMponents C3b and/or C4b. CD46 possesses four SCR doMains and the aiM of this study was to characterize their interaction with M Protein. Following confirMation of the M6 Protein-dependent interaction between GAS and huMan keratinocytes, we deMonstrated that M6 Protein binds soluble recoMbinant CD46 Protein and to a CD46 construct containing only SCRs 3 and 4. M6 Protein did not bind to soluble recoMbinant CD46 chiMeric Proteins that had the third and/or fourth SCR doMains replaced with the corresponding doMains froM another coMpleMent regulator, CD55 (decay-accelerating factor). HoMology-based Molecular Modeling of CD46 SCRs 3 and 4 revealed a cluster of positively charged residues between the interface of these SCR doMains siMilar to the verified M Protein binding sites on the plasMa coMpleMent regulators factor H and C4b-binding Protein. The presence of excess M6 Protein did not inhibit the cofactor activity of CD46 and the presence of excess C3b did not inhibit the ability of CD46 to bind M6 Protein by ELISA. In conclusion, 1) adherence of M6 GAS to keratinocytes is M Protein dependent and 2) a Major M Protein binding site is located within SCRs 3 and 4, probably at the interface of these two doMains, at a site distinct froM the C3b-binding and cofactor site of CD46.
Don W Cleveland - One of the best experts on this subject based on the ideXlab platform.
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the sars cov 2 nucleocapsid phosphoProtein forMs Mutually exclusive condensates with rna and the MeMbrane associated M Protein
Nature Communications, 2021Co-Authors: Digvijay Singh, Elizabeth Villa, Don W Cleveland, Yong Cao, Jolene K Diedrich, John R Yates, Kevin D CorbettAbstract:The Multifunctional nucleocapsid (N) Protein in SARS-CoV-2 binds the ~30 kb viral RNA genoMe to aid its packaging into the 80-90 nM MeMbrane-enveloped virion. The N Protein is coMposed of N-terMinal RNA-binding and C-terMinal diMerization doMains that are flanked by three intrinsically disordered regions. Here we deMonstrate that the N Protein's central disordered doMain drives phase separation with RNA, and that phosphorylation of an adjacent serine/arginine rich region Modulates the physical properties of the resulting condensates. In cells, N forMs condensates that recruit the stress granule Protein G3BP1, highlighting a potential role for N in G3BP1 sequestration and stress granule inhibition. The SARS-CoV-2 MeMbrane (M) Protein independently induces N Protein phase separation, and three-coMponent Mixtures of N + M + RNA forM condensates with Mutually exclusive coMpartMents containing N + M or N + RNA, including annular structures in which the M Protein coats the outside of an N + RNA condensate. These findings support a Model in which phase separation of the SARS-CoV-2 N Protein contributes both to suppression of the G3BP1-dependent host iMMune response and to packaging genoMic RNA during virion asseMbly.
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the sars cov 2 nucleocapsid phosphoProtein forMs Mutually exclusive condensates with rna and the MeMbrane associated M Protein
bioRxiv, 2020Co-Authors: Digvijay Singh, Elizabeth Villa, Don W Cleveland, Kevin D CorbettAbstract:The Multifunctional nucleocapsid (N) Protein in SARS-CoV-2 binds the ~30 kb viral RNA genoMe to aid its packaging into the 80-90nM MeMbrane-enveloped virion. The N Protein is coMposed of N-terMinal RNA-binding and C-terMinal diMerization doMains that are flanked by three intrinsically disordered regions. Here we deMonstrate that a centrally located 40 aMino acid intrinsically disordered doMain drives phase separation of N Protein when bound to RNA, with the Morphology of the resulting condensates affected by inclusion in the RNA of the putative SARS-CoV-2 packaging signal. The SARS-CoV-2 M Protein, norMally eMbedded in the virion MeMbrane with its C-terMinus extending into the virion core, independently induces N Protein phase separation that is dependent on the N Protein's C-terMinal diMerization doMain and disordered region. Three-coMponent Mixtures of N+M+RNA forM condensates with Mutually exclusive coMpartMents containing N+M or N+RNA, including spherical annular structures in which the M Protein coats the outside of an N+RNA condensate. These findings support a Model in which phase separation of the N Protein with both the viral genoMic RNA and the SARS-CoV-2 M Protein facilitates RNA packaging and virion asseMbly.
