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PLoS Pathog ; 15(10): e1008079, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31603949


Interferon-inducible p200 family protein IFI204 was reported to be involved in DNA sensing, and subsequently induces the production of type I interferons and proinflammatory mediators. However, its function in the regulation of antiviral innate immune signaling pathway remains unclear. Here we reported a novel role of IFI204 that specifically inhibits the IRF7-mediated type I interferons response during viral infection. IFI204 and other p200 family proteins are highly expressed in mouse hepatitis coronavirus-infected bone marrow-derived dendritic cells. The abundant IFI204 could significantly interact with IRF7 in nucleus by its HIN domain and prevent the binding of IRF7 with its corresponding promoter. Moreover, other p200 family proteins that possess HIN domain could also inhibit the IRF7-mediated type I interferons. These results reveal that, besides the positive regulation function in type I interferon response at the early stage of DNA virus infection, the interferon-inducible p200 family proteins such as IFI204 could also negatively regulate the IRF7-mediated type I interferon response after RNA virus infection to avoid unnecessary host damage from hyper-inflammatory responses.

Infecções por Coronavirus/imunologia , Coronavirus/imunologia , Fator Regulador 7 de Interferon/metabolismo , Interferon Tipo I/imunologia , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Células 3T3 , Células A549 , Animais , Linhagem Celular , Infecções por Coronavirus/patologia , Células HEK293 , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Inflamação/patologia , Fator Regulador 7 de Interferon/genética , Camundongos , Células RAW 264.7
Anal Chem ; 91(16): 10477-10483, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31318193


RNA molecules harbor diverse chemical modifications that play important regulatory roles in a variety of biological processes. Up to date, more than 150 modifications have been identified in various RNA species. Most of these modifications occurring in nucleic acids are the methylation of nucleic acids. It has been demonstrated that many of these methylation are reversible and undergo dynamic demethylation. Previous studies established that the demethylation of the two most important and prevalent modifications of 5-methylcytidine (m5C) and N6-methyladenosine (m6A) in nucleic acids is through the hydroxylation of m5C and m6A, forming 5-hydroxymethylcytidine (hm5C) and N6-hydroxymethyladenosine (hm6A), respectively. This indicates the hydroxylation of the methylated nucleosides may be a general pathway for the demethylation of nucleic acid methylation. However, few other hydroxylmethylation modifications have yet to be reported in existence in mammals. In the current study, we developed a neutral enzymatic digestion method for the mild digestion of nucleic acids, followed by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis. With the established method, we reported the existence of a new hydroxylmethylated nucleosides, N2-hydroxymethylguanosine (hm2G), in mammalian RNA. In addition, we found that the contents of hm2G, as well as N2-methylguanosine (m2G), showed significant differences between thyroid carcinoma tissues and tumor-adjacent normal tissues, indicating that m2G and hm2G in RNA may play certain roles in the carcinogenesis of thyroid carcinoma. Collectively, our study suggests that RNA hydroxylmethylation may be a new prevalent group of modifications existing in RNA, which expands the diversity of nucleic acid modifications and should exert regulatory functions in living organisms.

J Proteomics ; 206: 103435, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31279926


The neurotoxins of venomous scorpion act on ion channels. Whether these neurotoxins are retained in processed Buthus martensii Karsch scorpions used in traditional Chinese medicine materials is unknown. Comprehensive mass spectrometry-based proteomic characterization of functionally active toxins in the processed medicinal scorpion material revealed 22 full-length and 44 truncated thermostable potassium channel-modulatory toxins that preserved six conserved cysteine residues capable of forming the three disulfide bonds necessary for toxicity. Additionally, a broad spectrum of degraded toxin fragments was found, indicating their relative thermal instability which enabled toxicity reduction. Furthermore, the suppression of interleukin-2 (IL-2) production in Jurkat cells and the reduced delayed-type hypersensitivity (DTH) response demonstrated that the extracts have immunoregulatory activity both in vitro and in vivo. Our work describes the first "map" of functionally active scorpion toxins in processed scorpion medicinal material, which is helpful to unveil the pharmaceutical basis of the processed scorpion medicinal material in traditional Chinese medicine. BIOLOGICAL SIGNIFICANCE: Scorpions have been used as medicinal materials in China for more than one thousand years. This is an example of the well-known "Combat poison with poison" strategy common to traditional Chinese medicine. In the past 30 years, extensive investigations of Chinese scorpions have indicated that the neurotoxins in the scorpion venom are the main toxic components and they target various ion channels in cell membranes. However, whether these neurotoxins are retained in processed Buthus martensii Karsch scorpions used for traditional Chinese medicine remains unknown. Our study described the thermal stability and instability of potassium channel-modulatory neurotoxins in processed scorpions and helps to understand the pharmaceutical basis underling the strategy of "combat poison with poison to cure diseases".

Virol Sin ; 34(5): 549-562, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31134586


Dengue virus (DENV) infection is a worldwide public health threat. To date, the knowledge about the pathogenesis and progression of DENV infection is still limited. Combining global profiling based on proteomic analysis together with functional verification analysis is a powerful strategy to investigate the interplay between the virus and host cells. In the present study, quantitative proteomics has been applied to evaluate host responses (as indicated by altered proteins and modifications) in human cells (using K562 cell line) upon DENV-2 infection, as DENV-2 spreads most widely among all DENV serotypes. Comparative analysis was performed to define differentially expressed proteins in the infected cells compared to the mock-control, and it revealed critical pathogen-induced changes covering a broad spectrum of host cellular compartments and processes. We also discovered more dramatic changes (> 20%, 160 regulated phosphoproteins) in protein phosphorylation compared to protein expression (14%, 321 regulated proteins). Most of these proteins/phosphoproteins were involved in transcription regulation, RNA splicing and processing, immune system, cellular response to stimulus, and macromolecule biosynthesis. Western blot analysis was also performed to confirm the proteomic data. Potential roles of these altered proteins were discussed. The present study provides valuable large-scale protein-related information for elucidating the functional emphasis of host cell proteins and their post-translational modifications in virus infection, and also provides insight and protein evidence for understanding the general pathogenesis and pathology of DENV.

Vírus da Dengue/patogenicidade , Interações Hospedeiro-Patógeno/genética , Proteômica , Replicação Viral , Biologia Computacional , Vírus da Dengue/fisiologia , Humanos , Células K562 , Fosforilação , Processamento de Proteína Pós-Traducional