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  1 / 2403 MEDLINE  
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[PMID]:29188241
[Au] Autor:Mondal S; Chakraborty K; Bandyopadhyay S
[Ad] Endereço:Molecular Modeling Laboratory, Department of Chemistry, Indian Institute of Technology, Kharagpur-721302, India. sanjoy@chem.iitkgp.ernet.in.
[Ti] Título:Microscopic understanding of the conformational features of a protein-DNA complex.
[So] Source:Phys Chem Chem Phys;19(48):32459-32472, 2017 Dec 13.
[Is] ISSN:1463-9084
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protein-DNA interactions play crucial roles in different biological processes. Binding of a protein to its target DNA is the key step at different stages of genetic activities. In this article, we have carried out atomistic molecular dynamics simulations to understand the microscopic conformational and dynamical features of the N-terminal domain of the λ-repressor protein and its operator DNA in their complexed state. The calculations revealed that the overall flexibility of the protein and the DNA components reduces due to complex formation. In particular, increased ordering of the DNA sugar rings bound to the protein is found to be associated with modified ring puckering. Attempts have been made to study the effect of complexation on the internal motions of the protein and the DNA components. It is demonstrated that the non-uniform ordering of the side chains of lysine residues in the consensus sequence leads to differential behavior of the two monomers of the homodimeric protein.
[Mh] Termos MeSH primário: DNA/metabolismo
Proteínas Repressoras/metabolismo
Proteínas Virais Reguladoras e Acessórias/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Bacteriófago lambda/metabolismo
Sequência de Bases
Sítios de Ligação
DNA/química
Simulação de Dinâmica Molecular
Conformação de Ácido Nucleico
Ligação Proteica
Estrutura Terciária de Proteína
Proteínas Repressoras/química
Proteínas Virais Reguladoras e Acessórias/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Repressor Proteins); 0 (Viral Regulatory and Accessory Proteins); 0 (phage repressor proteins); 9007-49-2 (DNA)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171201
[St] Status:MEDLINE
[do] DOI:10.1039/c7cp05161a


  2 / 2403 MEDLINE  
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[PMID]:28961413
[Au] Autor:Faust TB; Binning JM; Gross JD; Frankel AD
[Ad] Endereço:Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158; email: tybifa@gmail.com , frankel@cgl.ucsf.edu.
[Ti] Título:Making Sense of Multifunctional Proteins: Human Immunodeficiency Virus Type 1 Accessory and Regulatory Proteins and Connections to Transcription.
[So] Source:Annu Rev Virol;4(1):241-260, 2017 Sep 29.
[Is] ISSN:2327-0578
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Viruses are completely dependent upon cellular machinery to support replication and have therefore developed strategies to co-opt cellular processes to optimize infection and counter host immune defenses. Many viruses, including human immunodeficiency virus type 1 (HIV-1), encode a relatively small number of genes. Viruses with limited genetic content often encode multifunctional proteins that function at multiple stages of the viral replication cycle. In this review, we discuss the functions of HIV-1 regulatory (Tat and Rev) and accessory (Vif, Vpr, Vpu, and Nef) proteins. Each of these proteins has a highly conserved primary activity; however, numerous additional activities have been attributed to these viral proteins. We explore the possibility that HIV-1 proteins leverage their multifunctional nature to alter host transcriptional networks to elicit a diverse set of cellular responses. Although these transcriptional effects appear to benefit the virus, it is not yet clear whether they are strongly selected for during viral evolution or are a ripple effect from the primary function. As our detailed knowledge of these viral proteins improves, we will undoubtedly uncover how the multifunctional nature of these HIV-1 regulatory and accessory proteins, and in particular their transcriptional functions, work to drive viral pathogenesis.
[Mh] Termos MeSH primário: Genes rev
Genes tat
HIV-1/genética
Proteínas do Vírus da Imunodeficiência Humana/metabolismo
Transcrição Genética
Proteínas Virais Reguladoras e Acessórias/metabolismo
[Mh] Termos MeSH secundário: HIV-1/química
HIV-1/fisiologia
Interações Hospedeiro-Patógeno
Proteínas do Vírus da Imunodeficiência Humana/genética
Seres Humanos
Proteínas Virais Reguladoras e Acessórias/genética
Replicação Viral
Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética
Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/genética
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Human Immunodeficiency Virus Proteins); 0 (Viral Regulatory and Accessory Proteins); 0 (nef Gene Products, Human Immunodeficiency Virus); 0 (vif Gene Products, Human Immunodeficiency Virus); 0 (vpr Gene Products, Human Immunodeficiency Virus); 0 (vpu protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170930
[St] Status:MEDLINE
[do] DOI:10.1146/annurev-virology-101416-041654


  3 / 2403 MEDLINE  
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[PMID]:28803141
[Au] Autor:Zhang N; Guo H; Yang J; Liu G; Li S; Li S; Wang D; Li R; Shu C; Xu H; Wei Z; Huang H; Zhang S; Gao P; Cen S; Markham R; Wang Y; Yu XF; Wei W
[Ad] Endereço:School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin Province 130000, China; Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, Jilin Province, China.
[Ti] Título:The poly-proline tail of SIVmac Vpx provides gain of function for resistance to a cryptic proteasome-dependent degradation pathway.
[So] Source:Virology;511:23-29, 2017 Nov.
[Is] ISSN:1096-0341
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The lentiviral accessory protein Vpx is critical for viral infection of myeloid cells and acts by hijacking CRL4(DCAF1) E3 ubiquitin ligase to induce the degradation of the host restriction factor SAMHD1. It has been observed that the sequences from HIV-2 and SIVsmm/SIVmac Vpx contain a poly-proline tail which is distinct from other SIV Vpx proteins. However, the role of this region in Vpx function is controversial. Herein, we found proteasome-dependent degradation of a Vpx mutant lacking the poly-proline tail in the nucleus in a CRL4(DCAF1) E3 ligase-independent fashion. Unlike wild-type Vpx, the poly-proline tail mutant Vpx is partly defective in enhancing viral infection in macrophages. Our findings suggest that during Vpx evolution, Vpx of the HIV-2/SIVsm/SIVmac lineage is targeted by a CRL4(DCAF1) E3 ligase-independent ubiquitination pathway, and have gained this interesting region, allowing them to maintain nuclear accumulation as part of their adaptation to host cell regulation.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/metabolismo
Interações Hospedeiro-Patógeno
Peptídeos/metabolismo
Complexo de Endopeptidases do Proteassoma/metabolismo
Vírus da Imunodeficiência Símia/efeitos dos fármacos
Proteínas Virais Reguladoras e Acessórias/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Peptides); 0 (VPX protein, Simian immunodeficiency virus); 0 (Viral Regulatory and Accessory Proteins); 25191-13-3 (polyproline); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170814
[St] Status:MEDLINE


  4 / 2403 MEDLINE  
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[PMID]:28758629
[Au] Autor:Florek D; Ehmann R; Kristen-Burmann C; Lemmermeyer T; Lochnit G; Ziebuhr J; Thiel HJ; Tekes G
[Ad] Endereço:1​Institute of Virology, Justus Liebig University Giessen, Germany.
[Ti] Título:Identification and characterization of a Golgi retention signal in feline coronavirus accessory protein 7b.
[So] Source:J Gen Virol;98(8):2017-2029, 2017 Aug.
[Is] ISSN:1465-2099
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Feline coronaviruses encode five accessory proteins with largely elusive functions. Here, one of these proteins, called 7b (206 residues), was investigated using a reverse genetic approach established for feline infectious peritonitis virus (FIPV) strain 79-1146. Recombinant FIPVs (rFPIVs) expressing mutant and/or FLAG-tagged forms of 7b were generated and used to investigate the expression, processing, glycosylation, localization and trafficking of the 7b protein in rFIPV-infected cells, focusing on a previously predicted ER retention signal, KTEL, at the C-terminus of 7b. The study revealed that 7b is N-terminally processed by a cellular signalase. The cleavage site, 17-Ala|Thr-18, was unambiguously identified by N-terminal sequence analysis of a 7b processing product purified from rFIPV-infected cells. Based on this information, rFIPVs expressing FLAG-tagged 7b proteins were generated and the effects of substitutions in the C-terminal 202KTEL206 sequence were investigated. The data show that (i) 7b localizes to and is retained in the medial- and/or trans-Golgi compartment, (ii) the C-terminal KTEL sequence acts as a Golgi [rather than an endoplasmic reticulum (ER)] retention signal, (iii) minor changes in the KTEL motif (such as KTE, KTEV, or the addition of a C-terminal tag) abolish Golgi retention, resulting in relocalization and secretion of 7b, and (iv) a KTEL-to-KDEL replacement causes retention of 7b in the ER of rFIPV-infected feline cells. Taken together, this study provides interesting new insights into an efficient Golgi retention signal that controls the cellular localization and trafficking of the FIPV 7b protein in virus-infected feline cells.
[Mh] Termos MeSH primário: Coronavirus Felino/metabolismo
Peritonite Infecciosa Felina/virologia
Complexo de Golgi/virologia
Proteínas Virais Reguladoras e Acessórias/metabolismo
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Sequência de Aminoácidos
Animais
Gatos
Coronavirus Felino/química
Coronavirus Felino/genética
Glicosilação
Complexo de Golgi/ultraestrutura
Dados de Sequência Molecular
Sinais Direcionadores de Proteínas
Transporte Proteico
Proteínas Virais Reguladoras e Acessórias/química
Proteínas Virais Reguladoras e Acessórias/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Sorting Signals); 0 (Viral Regulatory and Accessory Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE
[do] DOI:10.1099/jgv.0.000879


  5 / 2403 MEDLINE  
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[PMID]:28724765
[Au] Autor:Dyson OF; Pagano JS; Whitehurst CB
[Ad] Endereço:Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
[Ti] Título:The Translesion Polymerase Pol η Is Required for Efficient Epstein-Barr Virus Infectivity and Is Regulated by the Viral Deubiquitinating Enzyme BPLF1.
[So] Source:J Virol;91(19), 2017 Oct 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Epstein-Barr virus (EBV) infection and lytic replication are known to induce a cellular DNA damage response. We previously showed that the virally encoded BPLF1 protein interacts with and regulates several members of the translesion synthesis (TLS) pathway, a DNA damage tolerance pathway, and that these cellular factors enhance viral infectivity. BPLF1 is a late lytic cycle gene, but the protein is also packaged in the viral tegument, indicating that BPLF1 may function both early and late during infection. The BPLF1 protein expresses deubiquitinating activity that is strictly conserved across the ; mutation of the active site cysteine results in a loss of enzymatic activity. Infection with an EBV BPLF1 knockout virus results in decreased EBV infectivity. Polymerase eta (Pol η), a specialized DNA repair polymerase, functions in TLS and allows for DNA replication complexes to bypass lesions in DNA. Here we report that BPLF1 interacts with Pol η and that Pol η protein levels are increased in the presence of functional BPLF1. BPLF1 promotes a nuclear relocalization of Pol η molecules which are focus-like in appearance, consistent with the localization observed when Pol η is recruited to sites of DNA damage. Knockdown of Pol η resulted in decreased production of infectious virus, and further, Pol η was found to bind to EBV DNA, suggesting that it may allow for bypass of damaged viral DNA during its replication. The results suggest a mechanism by which EBV recruits cellular repair factors, such as Pol η, to sites of viral DNA damage via BPLF1, thereby allowing for efficient viral DNA replication. Epstein-Barr virus is the causative agent of infectious mononucleosis and infects approximately 90% of the world's population. It causes lymphomas in individuals with acquired and innate immune disorders and is strongly associated with Hodgkin's lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphomas, nasopharyngeal carcinoma (NPC), and lymphomas that develop in organ transplant recipients. Cellular DNA damage is a major determinant in the establishment of oncogenic processes and is well studied, but there are few studies of endogenous repair of viral DNA. This work evaluates how EBV's BPLF1 protein and its conserved deubiquitinating activity regulate the cellular DNA repair enzyme polymerase eta and recruit it to potential sites of viral damage and replication, resulting in enhanced production of infectious virus. These findings help to establish how EBV enlists and manipulates cellular DNA repair factors during the viral lytic cycle, contributing to efficient infectious virion production.
[Mh] Termos MeSH primário: Dano ao DNA/genética
Reparo do DNA/genética
Replicação do DNA/genética
DNA Polimerase Dirigida por DNA/genética
Enzimas Desubiquitinantes/genética
Herpesvirus Humano 4/genética
Proteínas Virais Reguladoras e Acessórias/genética
[Mh] Termos MeSH secundário: Linhagem Celular
DNA Viral/genética
DNA Viral/metabolismo
Infecções por Vírus Epstein-Barr/patologia
Infecções por Vírus Epstein-Barr/virologia
Dosagem de Genes/genética
Células HEK293
Herpesvirus Humano 4/patogenicidade
Seres Humanos
Antígeno Nuclear de Célula em Proliferação/genética
Interferência de RNA
RNA Interferente Pequeno/genética
Proteínas Virais Reguladoras e Acessórias/metabolismo
Replicação Viral/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BPLF1 protein, Epstein-Barr virus); 0 (DNA, Viral); 0 (Proliferating Cell Nuclear Antigen); 0 (RNA, Small Interfering); 0 (Viral Regulatory and Accessory Proteins); EC 2.7.7.7 (DNA-Directed DNA Polymerase); EC 2.7.7.7 (Rad30 protein); EC 3.4.19.12 (Deubiquitinating Enzymes)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE


  6 / 2403 MEDLINE  
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[PMID]:28714684
[Au] Autor:Chao SH; Schäfer J; Gruebele M
[Ad] Endereço:Department of Physics, University of Illinois , Urbana, Illinois 61801, United States.
[Ti] Título:The Surface of Protein λ Can Act as a Template for Recurring Poly(ethylene glycol) Structure.
[So] Source:Biochemistry;56(42):5671-5678, 2017 Oct 24.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PEGylated proteins play an increasingly important role in pharmaceutical drug delivery. We recently showed that short poly(ethylene glycol) (PEG) chains can affect protein structure, even when they are not making extensive contact with the protein surface. In contrast, PEG is generally thought to form a relatively unstructured coil, and its compactness depends on solvent conditions. Here we test whether a host protein could allow PEG to form recurrent structural motifs while the PEG chain is in contact with the protein surface. We link a PEG oligomer (n = 45) to one of two nearly opposite locations on the small α-helical protein λ to investigate this question. We first demonstrate experimentally that in these particular positions, PEG does not significantly affect the thermodynamic stability or folding kinetics of λ . We then use several all-atom molecular dynamics (MD) simulations 1 µs in duration to show how PEG equilibrates between states extending into the solvent and states packed onto the protein surface. The packing reveals recurring structures, including persistent hydrogen bond and hydrophobic contact patterns that appear multiple times. Some interactions of PEG with surface lysines are best described as an "intermittent slithering" motion of the PEG around the side chain, as seen in short MD movies. Thus, PEG achieves a variety of metastable organized structures on the protein surface, somewhere between a random globule and true folding. We also investigated the PEG-protein interaction in the unfolded state of the protein. We find that PEG has a propensity to stabilize certain helices of λ , no matter which of the two positions it was attached to. Thus, sufficiently long PEG chains are organized by the protein surface and in turn interact with certain elements of protein structure more than others, even when PEG is attached to very different sites.
[Mh] Termos MeSH primário: Simulação de Dinâmica Molecular
Polietilenoglicóis/química
Dobramento de Proteína
Proteínas Repressoras/química
Proteínas Virais Reguladoras e Acessórias/química
[Mh] Termos MeSH secundário: Ligações de Hidrogênio
Interações Hidrofóbicas e Hidrofílicas
Cinética
Estrutura Secundária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Repressor Proteins); 0 (Viral Regulatory and Accessory Proteins); 0 (phage repressor proteins); 30IQX730WE (Polyethylene Glycols); U076Q6Q621 (polyethylene glycol 1000)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00215


  7 / 2403 MEDLINE  
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[PMID]:28701393
[Au] Autor:Madhavi V; Wines BD; Amin J; Emery S; Lopez E; Kelleher A; Center RJ; Hogarth PM; Chung AW; Kent SJ; Stratov I; ENCORE1 Study Group; Sydney LTNP Study Group
[Ad] Endereço:Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia.
[Ti] Título:HIV-1 Env- and Vpu-Specific Antibody-Dependent Cellular Cytotoxicity Responses Associated with Elite Control of HIV.
[So] Source:J Virol;91(18), 2017 Sep 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Studying HIV-infected individuals who control HIV replication (elite controllers [ECs]) enables exploration of effective anti-HIV immunity. HIV Env-specific and non-Env-specific antibody-dependent cellular cytotoxicity (ADCC) may contribute to protection from progressive HIV infection, but the evidence is limited. We recruited 22 ECs and matched them with 44 viremic subjects. HIV Env- and Vpu-specific ADCC responses in sera were studied using a novel enzyme-linked immunosorbent assay (ELISA)-based dimeric recombinant soluble FcγRIIIa (rsFcγRIIIa)-binding assay, surface plasmon resonance, antibody-dependent natural killer (NK) cell activation assays, and ADCC-mediated killing assays. ECs had higher levels of HIV Env-specific antibodies capable of binding FcγRIIIa, activating NK cells, and mediating granzyme B activity (all < 0.01) than viremic subjects. ECs also had higher levels of antibodies against a C-terminal 13-mer Vpu peptide capable of mediating FcγRIIIa binding and NK cell activation than viremic subjects (both < 0.05). Our data associate Env-specific and Vpu epitope-specific ADCC in effective immune responses against HIV among ECs. Our findings have implications for understanding the role of ADCC in HIV control. Understanding immune responses associated with elite control of HIV may aid the development of immunotherapeutic and vaccine strategies for controlling HIV infection. Env is a major HIV protein target of functional antibody responses that are heightened in ECs. Interestingly, EC antibodies also target Vpu, an accessory protein crucial to HIV, which degrades CD4 and antagonizes tetherin. Antibodies specific to Vpu are a common feature of the immune response of ECs that may prove to be of functional importance to the design of improved ADCC-based immunotherapy and preventative HIV vaccines.
[Mh] Termos MeSH primário: Citotoxicidade Celular Dependente de Anticorpos
Anticorpos Anti-HIV/sangue
Infecções por HIV/imunologia
Proteínas do Vírus da Imunodeficiência Humana/imunologia
Proteínas Virais Reguladoras e Acessórias/imunologia
Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
[Mh] Termos MeSH secundário: Testes Imunológicos de Citotoxicidade
Ensaio de Imunoadsorção Enzimática
Sobreviventes de Longo Prazo ao HIV
Ressonância de Plasmônio de Superfície
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Antibodies); 0 (Human Immunodeficiency Virus Proteins); 0 (Viral Regulatory and Accessory Proteins); 0 (env Gene Products, Human Immunodeficiency Virus); 0 (vpu protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170714
[St] Status:MEDLINE


  8 / 2403 MEDLINE  
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[PMID]:28679761
[Au] Autor:Bharaj P; Atkins C; Luthra P; Giraldo MI; Dawes BE; Miorin L; Johnson JR; Krogan NJ; Basler CF; Freiberg AN; Rajsbaum R
[Ad] Endereço:Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
[Ti] Título:The Host E3-Ubiquitin Ligase TRIM6 Ubiquitinates the Ebola Virus VP35 Protein and Promotes Virus Replication.
[So] Source:J Virol;91(18), 2017 Sep 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ebola virus (EBOV), a member of the family, is a highly pathogenic virus that causes severe hemorrhagic fever in humans and is responsible for epidemics throughout sub-Saharan, central, and West Africa. The EBOV genome encodes VP35, an important viral protein involved in virus replication by acting as an essential cofactor of the viral polymerase as well as a potent antagonist of the host antiviral type I interferon (IFN-I) system. By using mass spectrometry analysis and coimmunoprecipitation assays, we show here that VP35 is ubiquitinated on lysine 309 (K309), a residue located on its IFN antagonist domain. We also found that VP35 interacts with TRIM6, a member of the E3-ubiquitin ligase tripartite motif (TRIM) family. We recently reported that TRIM6 promotes the synthesis of unanchored K48-linked polyubiquitin chains, which are not covalently attached to any protein, to induce efficient antiviral IFN-I-mediated responses. Consistent with this notion, VP35 also associated noncovalently with polyubiquitin chains and inhibited TRIM6-mediated IFN-I induction. Intriguingly, we also found that TRIM6 enhances EBOV polymerase activity in a minigenome assay and TRIM6 knockout cells have reduced replication of infectious EBOV, suggesting that VP35 hijacks TRIM6 to promote EBOV replication through ubiquitination. Our work provides evidence that TRIM6 is an important host cellular factor that promotes EBOV replication, and future studies will focus on whether TRIM6 could be targeted for therapeutic intervention against EBOV infection. EBOV belongs to a family of highly pathogenic viruses that cause severe hemorrhagic fever in humans and other mammals with high mortality rates (40 to 90%). Because of its high pathogenicity and lack of licensed antivirals and vaccines, EBOV is listed as a tier 1 select-agent risk group 4 pathogen. An important mechanism for the severity of EBOV infection is its suppression of innate immune responses. The EBOV VP35 protein contributes to pathogenesis, because it serves as an essential cofactor of the viral polymerase as well as a potent antagonist of innate immunity. However, how VP35 function is regulated by host cellular factors is poorly understood. Here, we report that the host E3-ubiquitin ligase TRIM6 promotes VP35 ubiquitination and is important for efficient virus replication. Therefore, our study identifies a new host factor, TRIM6, as a potential target in the development of antiviral drugs against EBOV.
[Mh] Termos MeSH primário: Ebolavirus/fisiologia
Interações Hospedeiro-Patógeno
Proteínas com Motivo Tripartido/metabolismo
Ubiquitina-Proteína Ligases/metabolismo
Ubiquitinação
Proteínas Virais Reguladoras e Acessórias/metabolismo
Replicação Viral
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Seres Humanos
Imunoprecipitação
Espectrometria de Massas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Tripartite Motif Proteins); 0 (VP35 protein, filovirus); 0 (Viral Regulatory and Accessory Proteins); EC 2.3.2.27 (TRIM6 protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE


  9 / 2403 MEDLINE  
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[PMID]:28659479
[Au] Autor:Zhu T; Song H; Peng R; Shi Y; Qi J; Gao GF
[Ad] Endereço:Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China.
[Ti] Título:Crystal Structure of the Marburg Virus Nucleoprotein Core Domain Chaperoned by a VP35 Peptide Reveals a Conserved Drug Target for Filovirus.
[So] Source:J Virol;91(18), 2017 Sep 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Filovirus nucleoprotein (NP), viral protein 35 (VP35), and polymerase L are essential for viral replication and nucleocapsid formation. Here, we identify a 28-residue peptide (NP binding peptide [NPBP]) from Marburg virus (MARV) VP35 through sequence alignment with previously identified Ebola virus (EBOV) NPBP, which bound to the core region (residues 18 to 344) of the N-terminal portion of MARV NP with high affinity. The crystal structure of the MARV NP core/NPBP complex at a resolution of 2.6 Å revealed that NPBP binds to the C-terminal region of the NP core via electrostatic and nonpolar interactions. Further structural analysis revealed that the MARV and EBOV NP cores hold a conserved binding pocket for NPBP, and this pocket could serve as a promising target for the design of universal drugs against filovirus infection. In addition, cross-binding assays confirmed that the NP core of MARV or EBOV can bind the NPBP from the other virus, although with moderately reduced binding affinities that result from termini that are distinct between the MARV and EBOV NPBPs. Historically, Marburg virus (MARV) has caused severe disease with up to 90% lethality. Among the viral proteins produced by MARV, NP and VP35 are both multifunctional proteins that are essential for viral replication. In its relative, Ebola virus (EBOV), an N-terminal peptide from VP35 binds to the NP N-terminal region with high affinity. Whether this is a common mechanism among filoviruses is an unsolved question. Here, we present the crystal structure of a complex that consists of the core domain of MARV NP and the NPBP peptide from VP35. As we compared MARV NPBP with EBOV NPBP, several different features at the termini were identified. Although these differences reduce the affinity of the NP core for NPBPs across genera, a conserved pocket in the C-terminal region of the NP core makes cross-species binding possible. Our results expand our knowledge of filovirus NP-VP35 interactions and provide more details for therapeutic intervention.
[Mh] Termos MeSH primário: Marburgvirus/química
Ribonucleoproteínas/química
Ribonucleoproteínas/metabolismo
Proteínas Virais/química
Proteínas Virais/metabolismo
Proteínas Virais Reguladoras e Acessórias/química
Proteínas Virais Reguladoras e Acessórias/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Cristalografia por Raios X
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ribonucleoproteins); 0 (VP35 protein, filovirus); 0 (Viral Proteins); 0 (Viral Regulatory and Accessory Proteins); 145717-56-2 (nucleoprotein, Marburg virus)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE


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[PMID]:28636653
[Au] Autor:Dilley KA; Voorhies AA; Luthra P; Puri V; Stockwell TB; Lorenzi H; Basler CF; Shabman RS
[Ad] Endereço:Virology Group, J. Craig Venter Institute, Rockville, Maryland, United States of America.
[Ti] Título:The Ebola virus VP35 protein binds viral immunostimulatory and host RNAs identified through deep sequencing.
[So] Source:PLoS One;12(6):e0178717, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ebola virus and Marburg virus are members of the Filovirdae family and causative agents of hemorrhagic fever with high fatality rates in humans. Filovirus virulence is partially attributed to the VP35 protein, a well-characterized inhibitor of the RIG-I-like receptor pathway that triggers the antiviral interferon (IFN) response. Prior work demonstrates the ability of VP35 to block potent RIG-I activators, such as Sendai virus (SeV), and this IFN-antagonist activity is directly correlated with its ability to bind RNA. Several structural studies demonstrate that VP35 binds short synthetic dsRNAs; yet, there are no data that identify viral immunostimulatory RNAs (isRNA) or host RNAs bound to VP35 in cells. Utilizing a SeV infection model, we demonstrate that both viral isRNA and host RNAs are bound to Ebola and Marburg VP35s in cells. By deep sequencing the purified VP35-bound RNA, we identified the SeV copy-back defective interfering (DI) RNA, previously identified as a robust RIG-I activator, as the isRNA bound by multiple filovirus VP35 proteins, including the VP35 protein from the West African outbreak strain (Makona EBOV). Moreover, RNAs isolated from a VP35 RNA-binding mutant were not immunostimulatory and did not include the SeV DI RNA. Strikingly, an analysis of host RNAs bound by wild-type, but not mutant, VP35 revealed that select host RNAs are preferentially bound by VP35 in cell culture. Taken together, these data support a model in which VP35 sequesters isRNA in virus-infected cells to avert RIG-I like receptor (RLR) activation.
[Mh] Termos MeSH primário: Ebolavirus/fisiologia
Doença pelo Vírus Ebola/imunologia
Sequenciamento de Nucleotídeos em Larga Escala/métodos
Interações Hospedeiro-Patógeno/imunologia
RNA de Cadeia Dupla/metabolismo
Proteínas Virais Reguladoras e Acessórias/metabolismo
[Mh] Termos MeSH secundário: Doença pelo Vírus Ebola/genética
Doença pelo Vírus Ebola/virologia
Seres Humanos
Interferons/antagonistas & inibidores
Vírus Sendai/genética
Vírus Sendai/imunologia
Transdução de Sinais
Proteínas Virais Reguladoras e Acessórias/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Double-Stranded); 0 (VP35 protein, filovirus); 0 (Viral Regulatory and Accessory Proteins); 9008-11-1 (Interferons)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170622
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0178717



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