A companion to a quasar at redshift 4.7

There is a growing consensus that the emergence of quasars at high redshifts is related to the onset of galaxy formation, suggesting that the detection of concentrations of gas accompanying such quasars should provide clues about the early history of galaxies. Quasar companions have been recently identified at redshifts up to $z \approx 3$. Here we report observations of Lyman-$\alpha$ emission (a tracer of ionised hydrogen) from the companion to a quasar at $z$=4.702, corresponding to a time when the Universe was less than ten per cent of its present age. We argue that most of the emission arises in a gaseous nebula that has been photoionised by the quasar, but an additional component of continuum light -perhaps quasar light scattered from dust in the companion body, or emission from young stars within the nebula- appears necessary to explain the observations. These observations may be indicative of the first stages in the assembly of galaxy-sized structures.Comment: 8 pages, 4 figures, plain LaTeX. Accepted for publication in Natur

Molecular mechanisms involved in HIV-1 transcriptional latency and reactivation: implications for the development of therapeutic strategies.

The persistence of latently HIV-infected cellular reservoirs, despite prolonged treatment with ART (antiretroviral therapy), represents the major hurdle to virus eradication. These latently infected cells are a permanent source for virus reactivation and lead to a rebound of the viral load after interruption of ART. Therefore, a greater understanding of the molecular mechanisms regulating viral latency and reactivation should lead to rational strategies aimed at purging the latent HIV reservoirs. Our laboratory is studying elements critical for the mechanisms of viral transcriptional reactivation including: 1) the transcription factor NF-kB, which is induced by proinflammatory cytokines (such as TNFalpha) and binds to two sites kB in the HIV-1 promoter region; 2) the specific remodeling of a single nucleosome (called nuc-1 and located immediately downstream of the HIV transcription start site under latency conditions) upon activation of the HIV-1 promoter; 3) post-translational acetylation of histones and of non-histone proteins (following treatment with deacetylase inhibitors [HDACi]), which induces viral transcription and nuc-1 remodeling. Recently, we have identified a new regulatory link between the first (NF-kB) and the third (protein acetylation) element by demonstrating a strong synergistic activation of HIV-1 promoter activity by TNFalpha (an inducer of NF-kB) and HDACi. In addition to the prototypical subtype B promoter, we have observed the TNFalpha/HDACi synergism with viral promoters from subtypes A through G of the HIV-1 major group, with a positive correlation between the number of kB sites present in the respective promoters and the amplitude of the TNFalpha/HDACi synergism. Importantly, the physiological relevance of this synergism was shown on HIV-1 replication in both acutely and latently HIV-infected cell lines. Therefore, our results open new therapeutic strategies aimed at administrating deacetylase inhibitor(s) together with continuous ART in order to force viral expression and decrease the pool of latently HIV-infected cellular reservoirs.Journal ArticleResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe

A role for APPL1 in tlr3/4-dependent TBK1 and IKKε activation in macrophages

Endosomes have important roles in intracellular signal transduction as a sorting platform. Signaling cascades from TLR engagement to IRF3-dependent gene transcription rely on endosomes, yet the proteins that specifically recruit IRF3-activating molécules to them are poorly defined. We show that adaptor protein containing a pleckstrin-homology domain, a phosphotyrosine-binding domain, and a leucine zipper motif (APPL)1, an early endosomal protein, is required for both TRIF- and retinoic acid–inducible gene 1–dependent signaling cascades to induce IRF3 activation. APPL1, but not early endosome Ag 1, deficiency impairs IRF3 target gene expression upon engagement of both TLR3 and TLR4 pathways, as well as in H1N1-infected macrophages. The IRF3-phosphorylating kinases TBK1 and IKK« are recruited to APPL1 endosomes in LPS-stimulated macrophages. Interestingly, APPL1 undergoes proteasome-mediated degradation through ERK1/2 to turn off signaling. APPL1 degradation is blocked when signaling through the endosome is inhibited by chloroquine or dynasore. Therefore, APPL1 endosomes are critical for IRF3-dependent gene expression in response to some viral and bacterial infections in macrophages. Those signaling pathways involve the signal-induced degradation of APPL1 to prevent aberrant IRF3-dependent gene expression linked to immune diseases

Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF.

Type I interferon gene induction relies on IKK-related kinase TBK1 and IKKepsilon-mediated phosphorylations of IRF3/7 through the Toll-like receptor-dependent signaling pathways. The scaffold proteins that assemble these kinase complexes are poorly characterized. We show here that TANK/ITRAF is required for the TBK1- and IKKepsilon-mediated IRF3/7 phosphorylations through some Toll-like receptor-dependent pathways and is part of a TRAF3-containing complex. Moreover, TANK is dispensable for the early phase of double-stranded RNA-mediated IRF3 phosphorylation. Interestingly, TANK is heavily phosphorylated by TBK1-IKKepsilon upon lipopolysaccharide stimulation and is also subject to lipopolysaccharide- and TBK1-IKKepsilon-mediated Lys(63)-linked polyubiquitination, a mechanism that does not require TBK1-IKKepsilon kinase activity. Thus, we have identified TANK as a scaffold protein that assembles some but not all IRF3/7-phosphorylating TBK1-IKKepsilon complexes and demonstrated that these kinases possess two functions, namely the phosphorylation of both IRF3/7 and TANK as well as the recruitment of an E3 ligase for Lys(63)-linked polyubiquitination of their scaffold protein, TANK.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

HDAC inhibitors and NF-kB inducers cooperate to reactivate latent HIV-1 proviruses in cellular reservoirs.

info:eu-repo/semantics/publishe

HDAC inhibitors and NF-kB inducers cooperate to reactivate latent HIV-1 proviruses in cellular reservoirs

info:eu-repo/semantics/publishe

Les kinases IKK et IKK-related sont-elles activées de façon similaire?

peer reviewedaudience: researcher, professionalThe IKKs, IKKa and IKKb, and the IKK-related kinases TBK1 and IKKe, play essential roles in innate immunity through signal-induced activation of NF-κB and IRF3/7, respectively. Although the signaling events within these pathways have been extensively studied, the mechanisms of IKK and IKK-related complex assembly and activation remain poorly defined. Recent data provide insight into the requirement for scaffold proteins in complex assembly; NEMO coordinates some IKK complexes, whereas TANK, NAP1 or SINTBAD assemble TBK1 and IKKe complexes. The different scaffold proteins undergo similar post-translational modifications, including phosphorylation and non-degradative polyubiquitylation. Moreover, increasing evidence suggests that distinct scaffold proteins assemble IKK and potentially TBK1 and IKKε sub-complexes in a stimulus-specific manner, which might be a mechanism to achieve specificity.Caractérisation des voies de signalisation TBK1-dépendante