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1.
PLoS Biol ; 19(3): e3001158, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33780434

RESUMO

Since its emergence in December 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread globally and become a major public health burden. Despite its close phylogenetic relationship to SARS-CoV, SARS-CoV-2 exhibits increased human-to-human transmission dynamics, likely due to efficient early replication in the upper respiratory epithelium of infected individuals. Since different temperatures encountered in the human upper and lower respiratory tract (33°C and 37°C, respectively) have been shown to affect the replication kinetics of several respiratory viruses, as well as host innate immune response dynamics, we investigated the impact of temperature on SARS-CoV-2 and SARS-CoV infection using the primary human airway epithelial cell culture model. SARS-CoV-2, in contrast to SARS-CoV, replicated to higher titers when infections were performed at 33°C rather than 37°C. Although both viruses were highly sensitive to type I and type III interferon pretreatment, a detailed time-resolved transcriptome analysis revealed temperature-dependent interferon and pro-inflammatory responses induced by SARS-CoV-2 that were inversely proportional to its replication efficiency at 33°C or 37°C. These data provide crucial insight on pivotal virus-host interaction dynamics and are in line with characteristic clinical features of SARS-CoV-2 and SARS-CoV, as well as their respective transmission efficiencies.


Assuntos
Perfilação da Expressão Gênica/métodos , Regulação Viral da Expressão Gênica/genética , SARS-CoV-2/genética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , Animais , Antivirais/farmacologia , Células Cultivadas , Chlorocebus aethiops , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Interferons/farmacologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/efeitos dos fármacos , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/fisiologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Especificidade da Espécie , Temperatura , Células Vero , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
2.
Nat Rev Cancer ; 16(5): 330-9, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27079803

RESUMO

The incidence of many types of cancer arising in organs with non-reproductive functions is significantly higher in male populations than in female populations, with associated differences in survival. Occupational and/or behavioural factors are well-known underlying determinants. However, cellular and molecular differences between the two sexes are also likely to be important. In this Opinion article, we focus on the complex interplay that sex hormones and sex chromosomes can have in intrinsic control of cancer-initiating cell populations, the tumour microenvironment and systemic determinants of cancer development, such as the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment.


Assuntos
Neoplasias/fisiopatologia , Caracteres Sexuais , Feminino , Hormônios Esteroides Gonadais/metabolismo , Humanos , Masculino , Transdução de Sinais
3.
Cell ; 157(7): 1698-711, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24910301

RESUMO

Germline-specific Piwi-interacting RNAs (piRNAs) protect animal genomes against transposons and are essential for fertility. piRNAs targeting active transposons are amplified by the ping-pong cycle, which couples Piwi endonucleolytic slicing of target RNAs to biogenesis of new piRNAs. Here, we describe the identification of a transient Amplifier complex that mediates biogenesis of secondary piRNAs in insect cells. Amplifier is nucleated by the DEAD box RNA helicase Vasa and contains the two Piwi proteins participating in the ping-pong loop, the Tudor protein Qin/Kumo and antisense piRNA guides. These components assemble on the surface of Vasa's helicase domain, which functions as an RNA clamp to anchor Amplifier onto transposon transcripts. We show that ATP-dependent RNP remodeling by Vasa facilitates transfer of 5' sliced piRNA precursors between ping-pong partners, and loss of this activity causes sterility in Drosophila. Our results reveal the molecular basis for the small RNA amplification that confers adaptive immunity against transposons.


Assuntos
Bombyx/metabolismo , Proteínas de Insetos/metabolismo , RNA Interferente Pequeno/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Bombyx/genética , Linhagem Celular , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Elementos de DNA Transponíveis , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Feminino , Proteínas de Insetos/genética , Mutação , Ovário/citologia , Ovário/metabolismo
4.
RNA ; 20(6): 773-81, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24757166

RESUMO

Piwi-interacting RNAs (piRNAs) guide Piwi Argonautes to suppress transposon activity in animal gonads. Known piRNA populations are extremely complex, with millions of individual sequences present in a single organism. Despite this complexity, specific Piwi proteins incorporate piRNAs with distinct nucleotide- and transposon strand-biases (antisense or sense) of unknown origin. Here, we examined the contribution of structural domains in Piwi proteins toward defining these biases. We report the first crystal structure of the MID domain from a Piwi Argonaute and use docking experiments to show its ability to specify recognition of 5' uridine (1U-bias) of piRNAs. Mutational analyses reveal the importance of 5' end-recognition within the MID domain for piRNA biogenesis in vivo. Finally, domain-swapping experiments uncover an unexpected role for the MID-PIWI module of a Piwi protein in dictating the transposon strand-orientation of its bound piRNAs. Our work identifies structural features that allow distinguishing individual Piwi members during piRNA biogenesis.


Assuntos
Proteínas Argonautas/química , Proteínas Argonautas/genética , Sequências Repetitivas Dispersas/genética , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , Animais , Bombyx/genética , Linhagem Celular , Cristalografia por Raios X , Escherichia coli/genética , Humanos , Camundongos , Nucleotídeos/genética
5.
Mol Cell ; 47(6): 970-9, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-22902560

RESUMO

Epigenetic silencing of transposons by Piwi-interacting RNAs (piRNAs) constitutes an RNA-based genome defense mechanism. Piwi endonuclease action amplifies the piRNA pool by generating new piRNAs from target transcripts by a poorly understood mechanism. Here, we identified mouse Fkbp6 as a factor in this biogenesis pathway delivering piRNAs to the Piwi protein Miwi2. Mice lacking Fkbp6 derepress LINE1 (L1) retrotransposon and display reduced DNA methylation due to deficient nuclear accumulation of Miwi2. Like other cochaperones, Fkbp6 associates with the molecular chaperone Hsp90 via its tetratricopeptide repeat (TPR) domain. Inhibition of the ATP-dependent Hsp90 activity in an insect cell culture model results in the accumulation of short antisense RNAs in Piwi complexes. We identify these to be byproducts of piRNA amplification that accumulate only in nuage-localized Piwi proteins. We propose that the chaperone machinery normally ejects these inhibitory RNAs, allowing turnover of Piwi complexes for their continued participation in piRNA amplification.


Assuntos
Elementos Nucleotídeos Longos e Dispersos , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas de Ligação a Tacrolimo/genética , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Proteínas Argonautas/biossíntese , Proteínas Argonautas/metabolismo , Linhagem Celular , Metilação de DNA , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Camundongos Knockout , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a Tacrolimo/deficiência
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