Epigenetic modifications of the herpesviral genome play a key role in the transcriptional control of latent and lytic genes during a productive viral lifecycle. In this study, we describe for the first time a comprehensive genome-wide ChIP-on-Chip analysis of the chromatin associated with the Kaposi's sarcoma-associated herpesvirus (KSHV) genome during latency and lytic reactivation. Depending on the gene expression class, different combinations of activating [acetylated H3 (AcH3) and H3K4me3] and repressive [H3K9me3 and H3K27me3] histone modifications are associated with the viral latent genome, which changes upon reactivation in a manner that is correlated with their expression. Specifically, both the activating marks co-localize on the KSHV latent genome, as do the repressive marks. However, the activating and repressive histone modifications are mutually exclusive of each other on the bulk of the latent KSHV genome. The genomic region encoding the IE genes ORF50 and ORF48 possesses the features of a bivalent chromatin structure characterized by the concomitant presence of the activating H3K4me3 and the repressive H3K27me3 marks during latency, which rapidly changes upon reactivation with increasing AcH3 and H3K4me3 marks and decreasing H3K27me3. Furthermore, EZH2, the H3K27me3 histone methyltransferase of the Polycomb group proteins (PcG), colocalizes with the H3K27me3 mark on the entire KSHV genome during latency, whereas RTA-mediated reactivation induces EZH2 dissociation from the genomic regions encoding IE and E genes concurrent with decreasing H3K27me3 level and increasing IE/E lytic gene expression. Moreover, either the inhibition of EZH2 expression by a small molecule inhibitor DZNep and RNAi knockdown, or the expression of H3K27me3-specific histone demethylases apparently induced the KSHV lytic gene expression cascade. These data indicate that histone modifications associated with the KSHV latent genome are involved in the regulation of latency and ultimately in the control of the temporal and sequential expression of the lytic gene cascade. In addition, the PcG proteins play a critical role in the control of KSHV latency by maintaining a reversible heterochromatin on the KSHV lytic genes. Thus, the regulation of the spatial and temporal association of the PcG proteins with the KSHV genome may be crucial for propagating the KSHV lifecycle.
Herpesvirus-associated ubiquitin specific protease (HAUSP) regulates the stability of p53 and MDM2, implicating HAUSP as a therapeutic target for tuning p53-mediated anti-tumor activity. Here, we report the structural analysis of HAUSP with Kaposi’s sarcoma-associated herpesvirus vIRF4 and the discovery of two vIRF4-derived peptides, vif1 and vif2, as potent and selective HAUSP antagonists. This analysis reveals a bilateral belt-type interaction resulting in inhibition of HAUSP. The vif1 peptide binds the HAUSP TRAF domain, competitively blocking substrate binding, while the vif2 peptide binds both the HAUSP TRAF and catalytic domains, robustly suppressing its deubiquitination activity. Consequently, peptide treatments comprehensively blocked HAUSP, leading to p53-dependent cell cycle arrest and apoptosis in culture and tumor regression in xenograft mouse model. Thus, the virus has developed a unique molecular strategy to target the HAUSP-MDM2-p53 pathway, and these virus-derived short peptides represent biologically active HAUSP antagonists.
Autophagy is a ubiquitous catabolic process that ensures organism’s well-being by sequestering a wide array of undesired intracellular constituents into double-membrane vesicles termed autophagosomes for lysosomal degradation. Interest in autophagy research has recently gained momentum as it is increasingly being recognized to play fundamental roles in diverse aspects of human pathophysiology including virus infection and its subsequent complications. This review discusses recent advances in autophagy studies with respect to virus infection and pathogenesis. A growing body of evidence suggests that the autophagy pathway and/or autophagy genes play pleiotropic functions in the host’s intrinsic, innate, and adaptive immune response against viruses. However, some viruses have evolved to encode virulence factors that evade or counteract the execution of autophagy. Furthermore, certain viruses are equipped to enhance autophagy or exploit the autophagy machinery for their replication and pathogenesis. A comprehensive understanding of the roles of autophagy pathway and autophagy genes during viral infection may enable the discovery of novel antiviral drug targets.
An efficient non-noble metal catalyst for the oxygen reduction reaction (ORR) is of great importance for the fabrication of cost-effective fuel cells. Nitrogen-doped carbons with various transition metal co-dopants have emerged as attractive candidates to replace the expensive platinum catalysts. Here we report the preparation of various copper- and nitrogen-doped carbon materials as highly efficient ORR catalysts by pyrolyzing porphyrin based metal organic frameworks and investigate the effects of air impurities during the thermal carbonization process. Our results indicate that the introduction of air impurities can significantly improve ORR activity in nitrogen-doped carbon and the addition of copper co-dopant further enhances the ORR activity to exceed that of platinum. Systematic structural characterization and electrochemical studies demonstrate that the air-impurity-treated samples show considerably higher surface area and electron transfer numbers, suggesting that the partial etching of the carbon by air leads to increased porosity and accessibility to highly active ORR sites. Our study represents the first example of using air or oxygen impurities to tailor the ORR activity of metal and nitrogen co-doped carbon materials and open up a new avenue to engineer the catalytic activity of these materials.
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