EBV Tegument Protein BNRF1 Disrupts DAXX-ATRX to Activate Viral Early Gene Transcription

Productive infection by herpesviruses involve the disabling of host-cell intrinsic defenses by viral encoded tegument proteins. Epstein-Barr Virus (EBV) typically establishes a non-productive, latent infection and it remains unclear how it confronts the host-cell intrinsic defenses that restrict viral gene expression. Here, we show that the EBV major tegument protein BNRF1 targets host-cell intrinsic defense proteins and promotes viral early gene activation. Specifically, we demonstrate that BNRF1 interacts with the host nuclear protein Daxx at PML nuclear bodies (PML-NBs) and disrupts the formation of the Daxx-ATRX chromatin remodeling complex. We mapped the Daxx interaction domain on BNRF1, and show that this domain is important for supporting EBV primary infection. Through reverse transcription PCR and infection assays, we show that BNRF1 supports viral gene expression upon early infection, and that this function is dependent on the Daxx-interaction domain. Lastly, we show that knockdown of Daxx and ATRX induces reactivation of EBV from latently infected lymphoblastoid cell lines (LCLs), suggesting that Daxx and ATRX play a role in the regulation of viral chromatin. Taken together, our data demonstrate an important role of BNRF1 in supporting EBV early infection by interacting with Daxx and ATRX; and suggest that tegument disruption of PML-NB-associated antiviral resistances is a universal requirement for herpesvirus infection in the nucleus

Evolutionary conservation and in vitro reconstitution of microsporidian iron–sulfur cluster biosynthesis

This work was supported by Marie Curie Postdoctoral Fellowships to T.A.W., E. H. and S. L., a European Research Council Advanced Investigator Grant (ERC-2010-AdG-268701) to T.M.E., and a Wellcome Trust Programme Grant (number 045404) to T.M.E. and J.M.L. R.L. acknowledges generous financial support from Deutsche Forschungsgemeinschaft (SFB 593, SFB 987, GRK 1216, LI 415/5), LOEWE program of state Hessen, Max-Planck Gesellschaft, von Behring-Röntgen StiftungMicrosporidians are a diverse group of obligate intracellular parasites that have minimized their genome content and simplified their sub-cellular structures by reductive evolution. Functional studies are limited because we lack reliable genetic tools for their manipulation. Here, we demonstrate that the cristae-deficient mitochondrion (mitosome) of the microsporidian Trachipleistophora hominis is the functional site of iron-sulphur cluster (ISC) assembly, which we suggest is the essential task of this organelle. Cell fractionation, fluorescence imaging and fine-scale immunoelectron microscopy demonstrate that mitosomes contain a complete pathway for [2Fe-2S] cluster biosynthesis that we biochemically reconstituted using purified recombinant mitosomal ISC proteins. Reconstitution proceeded as rapidly and efficiently as observed for yeast or fungal mitochondrial ISC components. Core components of the T. hominis cytosolic iron-sulphur protein assembly (CIA) pathway were also identified including the essential Cfd1-Nbp35 scaffold complex that assembles a [4Fe-4S] cluster as shown by spectroscopic methods in vitro. Phylogenetic analyses reveal that both the ISC and CIA biosynthetic pathways are predominantly bacterial, but their cytosolic and nuclear target Fe/S proteins are mainly archaeal. This mixed evolutionary history of the Fe/S-related proteins and pathways, and their strong conservation among highly reduced parasites, provides additional compelling evidence for the ancient chimeric ancestry of eukaryotes.Publisher PDFPeer reviewe

Pax5 and linker histone H1 coordinate DNA methylation and histone modifications in the 3 ' regulatory region of the immunoglobulin heavy chain locus

The 3' regulatory region ( 3' RR) of the murine immunoglobulin heavy chain (IgH) locus contains multiple DNase I-hypersensitive (hs) sites. Proximal sites hs3A, hs1.2, and hs3B are located in an extensive palindromic region and together with hs4 are associated with enhancers involved in the expression and class switch recombination of IgH genes. Distal hs5, -6, and -7 sites located downstream of hs4 comprise a potential insulator for the IgH locus. In pro-B cells, hs4 to -7 are associated with marks of active chromatin, while hs3A, hs1.2, and hs3B are not. Our analysis of DNA methylation-sensitive restriction sites of the 3' RR has revealed a similar modular pattern in pro-B cells; hs4 to -7 sites are unmethylated, while the palindromic region is methylated. This modular pattern of DNA methylation and histone modifications appears to be determined by at least two factors: the B-cell-specific transcription factor Pax5 and linker histone H1. In pre-B cells, a region beginning downstream of hs4 and extending into hs5 showed evidence of allele-specific demethylation associated with the expressed heavy chain allele. Palindromic enhancers become demethylated later in B-cell differentiation, in B and plasma cells

Combination of Organic-Based Reservoir Computing and Spiking Neuromorphic Systems for a Robust and Efficient Pattern Classification

Nowadays, neuromorphic systems based on memristors are considered promising approaches to the hardware realization of artificial intelligence systems with efficient information processing. However, a major bottleneck in the physical implementation of these systems is the strong dependence of their performance on the unavoidable variations (cycle-to-cycle, c2c, or device-to-device, d2d) of memristive devices. Recently, reservoir computing (RC) and spiking neuromorphic systems (SNSs) are separately proposed as valuable options to partially mitigate this problem. Herein, both approaches are combined to create a fully organic system based on 1) volatile polyaniline memristive devices for the reservoir layer and 2) nonvolatile parylene memristors for the SNS readout layer. This combination provides a simpler SNS training procedure compared with the formal neural networks and results in greater robustness to device variability, while ensuring the extraction and encoding of the input critical features (performed by the polyaniline reservoir) and the analysis and classification performed by the SNS layer. Furthermore, the spatiotemporal pattern recognition of the system brings us closer to the implementation of efficient and reliable brain-inspired computing systems built with partially unreliable analog elements