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1.
Cell Rep ; 42(12): 113558, 2023 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-38103200

RESUMEN

For virus infection of new host cells, the disassembly of the protective outer protein shell (capsid) is a critical step, but the mechanisms and host-virus interactions underlying the dynamic, active, and regulated uncoating process are largely unknown. Here, we develop an experimentally supported, multiscale kinetics model that elucidates mechanisms of influenza A virus (IAV) uncoating in cells. Biophysical modeling demonstrates that interactions between capsid M1 proteins, host histone deacetylase 6 (HDAC6), and molecular motors can physically break the capsid in a tug-of-war mechanism. Biochemical analysis and biochemical-biophysical modeling identify unanchored ubiquitin chains as essential and allow robust prediction of uncoating efficiency in cells. Remarkably, the different infectivity of two clinical strains can be ascribed to a single amino acid variation in M1 that affects binding to HDAC6. By identifying crucial modules of viral infection kinetics, the mechanisms and models presented here could help formulate novel strategies for broad-range antiviral treatment.


Asunto(s)
Virus de la Influenza A , Gripe Humana , Humanos , Desencapsidación Viral , Virus de la Influenza A/metabolismo , Ubiquitina/metabolismo , Proteínas de la Cápside/metabolismo , Replicación Viral , Interacciones Huésped-Patógeno
2.
Cell Cycle ; 15(5): 689-98, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27027999

RESUMEN

MicroRNAs (miRs) are short noncoding RNA molecules that regulate expression of target mRNAs. Many published sources provide information about miRs and their targets. However, bioinformatic tools elucidating higher level impact of the established total miR profiles, are still largely missing. Recently, we developed a method termed OncoFinder enabling quantification of the activities of intracellular molecular pathways basing on gene expression data. Here we propose a new technique, MiRImpact, which enables to link miR expression data with its estimated outcome on the regulation of molecular pathways, like signaling, metabolic, cytoskeleton rearrangement, and DNA repair pathways. MiRImpact uses OncoFinder rationale for pathway activity calculations, with the major distinctions that (i) it deals with the concentrations of miRs--known regulators of gene products participating in molecular pathways, and (ii) miRs are considered as negative regulators of target molecules, if other is not specified. MiRImpact operates with 2 types of databases: for molecular targets of miRs and for gene products participating in molecular pathways. We applied MiRImpact to compare regulation of human bladder cancer-specific signaling pathways at the levels of mRNA and miR expression. We took 2 most complete alternative databases of experimentally validated miR targets--miRTarBase and DianaTarBase, and an OncoFinder database featuring 2725 gene products and 271 signaling pathways. We showed that the impact of miRs is orthogonal to pathway regulation at the mRNA level, which stresses the importance of studying posttranscriptional regulation of gene expression. We also report characteristic set of miR and mRNA regulation features linked with bladder cancer.


Asunto(s)
MicroARNs/fisiología , Biología Computacional , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Interferencia de ARN , Transducción de Señal , Transcriptoma , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo
3.
Cell Cycle ; 15(24): 3378-3389, 2016 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-28051642

RESUMEN

Responses to human cytomegalovirus (HCMV) infection are largely individual and cell type specific. We investigated molecular profiles in 2 primary cell cultures of human fibroblasts, which are highly or marginally sensitive to HCMV infection, respectively. We screened expression of genes and microRNAs (miRs) at the early (3 hours) stage of infection. To assess molecular pathway activation profiles, we applied bioinformatic algorithms OncoFinder and MiRImpact. In both cell types, pathway regulation properties at mRNA and miR levels were markedly different. Surprisingly, in the infected highly sensitive cells, we observed a "freeze" of miR expression profiles compared to uninfected controls. Our results evidence that in the sensitive cells, HCMV blocks intracellular regulation of microRNA expression already at the earliest stage of infection. These data suggest somewhat new functions for HCMV products and demonstrate dependence of miR expression arrest on the host-encoded factors.


Asunto(s)
Infecciones por Citomegalovirus/metabolismo , Fibroblastos/metabolismo , Fibroblastos/virología , Regulación de la Expresión Génica , MicroARNs/genética , Adulto , Línea Celular , Fibroblastos/patología , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , MicroARNs/metabolismo , Reproducibilidad de los Resultados , Transducción de Señal/genética , Proteínas Virales/metabolismo
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