Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis that is closely associated with several human malignant diseases, while type I interferon (IFN-I) plays an important role against EBV infection. As we all know, EBV can encode some proteins to inhibit the production of IFN-I, but it’s not clear whether other proteins also take part in this progress. EBV early lytic protein BFRF1 is shown to be involved in viral maturation, however, whether BFRF1 participates in the host innate immune response is still not well known. In this study, we found BFRF1 could down-regulate sendai virus-induced IFN-β promoter activity and mRNA expression of IFN-β and ISG54 during BFRF1 plasmid transfection and EBV lytic infection, but BFRF1 could not affect the promoter activity of NF-κB or IRF7. Specifically, BFRF1 could co-localize and interact with IKKi. Although BFRF1 did not interfere the interaction between IKKi and IRF3, it could block the kinase activity of IKKi, which finally inhibited the phosphorylation, dimerization, and nuclear translocation of IRF3. Taken together, BFRF1 may play a critical role in disrupting the host innate immunity by suppressing IFN-β activity during EBV lytic cycle.
The sporoderm-broken spores of Ganoderma lucidum (G. lucidum) polysaccharide (BSGLP) have been demonstrated to inhibit carcinogenesis in several types of cancer. However, to the best of our knowledge, the anticancer effects of polysaccharides extracted from the newly developed sporoderm-removed spores of G. lucidum (RSGLP) have not been assessed. The present study first compared the anticancer effects of RSGLP and BSGLP in three gastric cancer cell lines and it was found that RSGLP was more potent than BSGLP in decreasing gastric cancer cell viability. RSGLP significantly induced apoptosis in AGS cells, accompanied by downregulation of Bcl-2 and pro-caspase-3 expression levels, and upregulation of cleaved-PARP. Furthermore, RSGLP increased LC3-II and p62 expression, indicative of induction of autophagy and disruption of autophagic flux in AGS cells. These results were further verified by combined treatment of AGS cells with the late-stage autophagy inhibitor chloroquine, or early-stage autophagy inducer rapamycin. Adenoviral transfection with mRFP-GFP-LC3 further confirmed that autophagic flux was inhibited by RSGLP in AGS cells. Finally, the present study demonstrated that the RSGLP-induced autophagy and disruption of autophagic flux disruption was, at least in part, responsible for RSGLP-induced apoptosis in AGS cells. The results of the present study demonstrated for the first time that RSGLP is more effective than BSGLP in inhibiting gastric cancer cell viability, and RSGLP may serve as a promising autophagy inhibitor in the management of gastric cancer.
The innate immune system is the first line of host defense against the invasion of pathogens. Among its mechanisms, IFN-I is an essential cytokine in the antiviral response, which can help the host eliminate a virus.
Epstein–Barr virus (EBV), the pathogen of several human malignancies, encodes many proteins required to be transported into the nucleus for viral DNA reproduction and nucleocapsids assembly in the lytic replication cycle. Here, fluorescence microscope, mutation analysis, interspecies heterokaryon assays, co-immunoprecipitation assay, RNA interference, and Western blot were performed to explore the nuclear import mechanism of EBV encoded BLLF2 protein. BLLF2 was shown to be a nucleocytoplasmic shuttling protein neither by a chromosomal region maintenance 1 (CRM1)- nor by a transporter associated with antigen processing (TAP)-dependent pathway. Yet, BLLF2’s two functional nuclear localization signals (NLSs), NLS1 (16KRQALETVPHPQNRGR31) and NLS2 (44RRPRPPVAKRRRFPR58), were identified, whereas the predicted NES was nonfunctional. Finally, BLLF2 was proven to transport into the nucleus via a Ran-dependent and importin β1-dependent pathway. This mechanism may contribute to a more extensive insight into the assembly and synthesis of EBV virions in the nucleus, thus affording a new direction for the treatment of viruses.
Background: Epstein-Barr virus (EBV), the pathogen of several human malignancies, encodes many proteins that require to be transported into the nucleus for viral DNA reproduction and nucleocapsids assembly in the lytic replication cycle. A nuclear membrane phosphoprotein encoded by EBV BLLF2, is believed to associate with viral DNA packaging and primary egress across the nuclear membrane. Results: Here, fluorescence microscope, mutation analysis, interspecies heterokaryon assays, co-immunoprecipitation assays and western blot were performed to explore the nuclear import mechanism of BLLF2. As results, BLLF2 was shown to be a nucleocytoplasmic shuttling protein, which was mediated neither by chromosomal region maintenance 1 (CRM1)- nor transporter associated with antigen processing (TAP)-dependent pathway. Yet, two functional nuclear localization signals (NLSs) of BLLF2, NLS1 (16KRQALETVPHPQNRGR31) and NLS2 (48PPVAKRRR58), were identified, whereas the predicted NES was nonfunctional. Finally, BLLF2 was proved to transport into the nucleus via Ran-dependent and importin β1-dependent pathway. Conclusions: This mechanism may contribute to a more extensive insight of the assembly and synthesis of EB virions in the nucleus, thus affording a new direction for the treatment of viruses.
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