174 research outputs found
The Epstein-Barr Virus Episome Maneuvers between Nuclear Chromatin Compartments during Reactivation.
The human genome is structurally organized in three-dimensional space to facilitate functional partitioning of transcription. We learned that the latent episome of the human Epstein-Barr virus (EBV) preferentially associates with gene-poor chromosomes and avoids gene-rich chromosomes. Kaposi's sarcoma-associated herpesvirus behaves similarly, but human papillomavirus does not. Contacts on the EBV side localize to OriP, the latent origin of replication. This genetic element and the EBNA1 protein that binds there are sufficient to reconstitute chromosome association preferences of the entire episome. Contacts on the human side localize to gene-poor and AT-rich regions of chromatin distant from transcription start sites. Upon reactivation from latency, however, the episome moves away from repressive heterochromatin and toward active euchromatin. Our work adds three-dimensional relocalization to the molecular events that occur during reactivation. Involvement of myriad interchromosomal associations also suggests a role for this type of long-range association in gene regulation.IMPORTANCE The human genome is structurally organized in three-dimensional space, and this structure functionally affects transcriptional activity. We set out to investigate whether a double-stranded DNA virus, Epstein-Barr virus (EBV), uses mechanisms similar to those of the human genome to regulate transcription. We found that the EBV genome associates with repressive compartments of the nucleus during latency and with active compartments during reactivation. This study advances our knowledge of the EBV life cycle, adding three-dimensional relocalization as a novel component to the molecular events that occur during reactivation. Furthermore, the data add to our understanding of nuclear compartments, showing that disperse interchromosomal interactions may be important for regulating transcription
Characteristics of HIV-1 gp120 molecules that bind ancestor, intermediate and mature forms of VRC01-like antibodies
Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.
Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses
Structural definition for a new modality of broad and potent antibody neutralization at the CD4-binding site on HIV-1 gp120
Recommended from our members
Building WF16: construction of a PPNA pisé structure in Southern Jordan
The Pre-Pottery Neolithic A (PPNA) period in Southwest Asia is essential for our understanding of the transition to sedentary, agricultural communities. Developments in architecture are key to understanding this transition, but many aspects of PPNA architecture remain elusive, such as construction techniques, the selection of building materials, and the functional use of space. The primary aim of the research described within this contribution was to build a PPNA-like structure in order to answer questions about PPNA architecture in general, while specifically addressing issues raised by the excavation of structures at the site of WF16, Southern Jordan. The second aim was to display a âPPNAâ building to visitors in Wadi Faynan to enhance their understanding of the period. The experimental construction based on one of the WF16 structures showed that 1) required materials can be acquired locally; 2) a construction technique using mud layers as described in this paper was likely used; 3) flat, or very slightly dome-shaped, roofs are functional and can also be used as a solid working platform; 4) the WF16 small semi-subterranean buildings appear inappropriate for housing a nuclear family unit
Pancreatic ÎČ-Cell Death in Response to Pro-Inflammatory Cytokines Is Distinct from Genuine Apoptosis
A reduction in functional ÎČ-cell mass leads to both major forms of diabetes; pro-inflammatory cytokines, such as interleukin-1beta (IL-1ÎČ) and gamma-interferon (Îł-IFN), activate signaling pathways that direct pancreatic ÎČ-cell death and dysfunction. However, the molecular mechanism of ÎČ-cell death in this context is not well understood. In this report, we tested the hypothesis that individual cellular death pathways display characteristic phenotypes that allow them to be distinguished by the precise biochemical and metabolic responses that occur during stimulus-specific initiation. Using 832/13 and INS-1E rat insulinoma cells and isolated rat islets, we provide evidence that apoptosis is unlikely to be the primary pathway underlying ÎČ-cell death in response to IL-1ÎČ+Îł-IFN. This conclusion was reached via the experimental results of several different interdisciplinary strategies, which included: 1) tandem mass spectrometry to delineate the metabolic differences between IL-1ÎČ+Îł-IFN exposure versus apoptotic induction by camptothecin and 2) pharmacological and molecular interference with either NF-ÎșB activity or apoptosome formation. These approaches provided clear distinctions in cell death pathways initiated by pro-inflammatory cytokines and bona fide inducers of apoptosis. Collectively, the results reported herein demonstrate that pancreatic ÎČ-cells undergo apoptosis in response to camptothecin or staurosporine, but not pro-inflammatory cytokines
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.
Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field
Delineating antibody recognition in polyclonal sera from patterns of HIV-1 isolate neutralization.
Serum characterization and antibody isolation are transforming our understanding of the humoral immune response to viral infection. Here, we show that epitope specificities of HIV-1âneutralizing antibodies in serum can be elucidated from the serum pattern of neutralization against a diverse panel of HIV-1 isolates. We determined âneutralization fingerprintsâ for 30 neutralizing antibodies on a panel of 34 diverse HIV-1 strains and showed that similarity in neutralization fingerprint correlated with similarity in epitope. We used these fingerprints to delineate specificities of
polyclonal sera from 24 HIV-1âinfected donors and a chimeric siman-human immunodeficiency virusâinfected macaque. Delineated specificities matched published specificities and were further confirmed by antibody isolation for two sera. Patterns of virus-isolate neutralization can thus afford a detailed epitope-specific understanding of neutralizing-antibody responses to viral infection
- âŠ