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Sainte-Foy-lès-Lyon, France

Lomonte P.,University Claude Bernard Lyon 1 | Lomonte P.,University of Lyon | Lomonte P.,Laboratoire dExcellence
Virologie | Year: 2014

After a primary infection, many viruses establish a latent infection and stay invisible for the host immune system until reactivation. To understand how a virus seemingly « under control » could reactivate and induce pathology, it is essential to understand the different cellular mechanisms implicated in the antiviral defense. Promyelocytic leukemia (PML) nuclear bodies (PML-NB) are nuclear relays of the antiviral response implicated in the nucleus-associated intrinsic antiviral defense. Many viruses interfere with the activity of the PML-NB, however not much is known about the capacity of these domains to interact with the nucleus incoming viral genomes. This review describes how a recent study of my team has enabled to decipher, in a physiological context, the role of the PML-NB in the detection, structuration and transcriptional control of the herpes simplex virus 1 (HSV-1). It opens new perspectives to understand how the antiviral response associated with nuclear domains could control many other viruses.

Antunes A.T.,University Utrecht | Goos Y.J.,University Utrecht | Pereboom T.C.,University Utrecht | Hermkens D.,University Utrecht | And 6 more authors.
PLoS Genetics | Year: 2015

Mutations in ribosomal protein (RP) genes can result in the loss of erythrocyte progenitor cells and cause severe anemia. This is seen in patients with Diamond-Blackfan anemia (DBA), a pure red cell aplasia and bone marrow failure syndrome that is almost exclusively linked to RP gene haploinsufficiency. While the mechanisms underlying the cytopenia phenotype of patients with these mutations are not completely understood, it is believed that stabilization of the p53 tumor suppressor protein may induce apoptosis in the progenitor cells. In stark contrast, tumor cells from zebrafish with RP gene haploinsufficiency are unable to stabilize p53 even when exposed to acute DNA damage despite transcribing wild type p53 normally. In this work we demonstrate that p53 has a limited role in eliciting the anemia phenotype of zebrafish models of DBA. In fact, we find that RP-deficient embryos exhibit the same normal p53 transcription, absence of p53 protein, and impaired p53 response to DNA damage as RP haploinsufficient tumor cells. Recently we reported that RP mutations suppress activity of the AKT pathway, and we show here that this suppression results in proteasomal degradation of p53. By re-activating the AKT pathway or by inhibiting GSK-3, a downstream modifier that normally represses AKT signaling, we are able to restore the stabilization of p53. Our work indicates that the anemia phenotype of zebrafish models of DBA is dependent on factors other than p53, and may hold clinical significance for both DBA and the increasing number of cancers revealing spontaneous mutations in RP genes. © 2015 Antunes et al.

Bertucci F.,CNRS Insular Research Center and Environment Observatory | Bertucci F.,University of Liege | Parmentier E.,University of Liege | Berten L.,CNRS Insular Research Center and Environment Observatory | And 4 more authors.
PLoS ONE | Year: 2015

As environmental sounds are used by larval fish and crustaceans to locate and orientate towards habitat during settlement, variations in the acoustic signature produced by habitats could provide valuable information about habitat quality, helping larvae to differentiate between potential settlement sites. However, very little is known about how acoustic signatures differ between proximate habitats. This study described within- and between-site differences in the sound spectra of five contiguous habitats at Moorea Island, French Polynesia: the inner reef crest, the barrier reef, the fringing reef, a pass and a coastal mangrove forest. Habitats with coral (inner, barrier and fringing reefs) were characterized by a similar sound spectrum with average intensities ranging from 70 to 78 dB re 1μPa.Hz-1. The mangrove forest had a lower sound intensity of 70 dB re 1μPa.Hz-1 while the pass was characterized by a higher sound level with an average intensity of 91 dB re 1μPa.Hz-1. Habitats showed significantly different intensities for most frequencies, and a decreasing intensity gradient was observed from the reef to the shore. While habitats close to the shore showed no significant diel variation in sound intensities, sound levels increased at the pass during the night and barrier reef during the day. These two habitats also appeared to be louder in the North than in the West. These findings suggest that daily variations in sound intensity and across-reef sound gradients could be a valuable source of information for settling larvae. They also provide further evidence that closely related habitats, separated by less than 1 km, can differ significantly in their spectral composition and that these signatures might be typical and conserved along the coast of Moorea. Copyright: © 2015 Bertucci et al.

Forand A.,French Institute of Health and Medical Research | Forand A.,University of Paris Descartes | Forand A.,Laboratoire dExcellence | Beck L.,French Institute of Health and Medical Research | And 18 more authors.
Blood | Year: 2013

The PIT1/SLC20A1 protein, a well-described sodium/phosphate cotransporter and retrovirus receptor, has been identified recently as a modular of proliferation and apoptosis in vitro. The targeted deletion of the PIT1 gene in mice revealed a lethal phenotype due to severe anemia attributed to defects in liver development. However, the presence of immature erythroid cells associated with impaired maturation of the globin switch led us to investigate the role of PIT1 in hematopoietic development. In the present study, specific deletion of PIT1 in the hematopoietic system and fetal liver transplantation experiments demonstrated that anemia was associated with an erythroid cell- autonomous defect. Moreover, anemia was not due to RBC destruction but rather to maturation defects. Because Erythroid Krüppel-like Factor (EKLF)-knockout mice showed similar maturation defects, we investigated the functional link between PIT1 and EKLF. We demonstrated that EKLF increases PIT1 expression during RBC maturation by binding to its promoter in vivo and that shRNA-driven depletion of either PIT1 or EKLF impairs erythroid maturation of G1E cells in vitro, whereas reexpression of PIT1 in EKLF-depleted G1E cells partially restores erythroid maturation. This is the first demonstration of a physiologic involvement of PIT1 in erythroid maturation in vivo. © 2013 by The American Society of Hematology.

Mahajan S.,University of Reunion Island | Mahajan S.,French Institute of Health and Medical Research | Mahajan S.,Laboratoire dExcellence | Mahajan S.,University of Nantes | And 8 more authors.
Protein Science | Year: 2015

The structural annotation of proteins with no detectable homologs of known 3D structure identified using sequence-search methods is a major challenge today. We propose an original method that computes the conditional probabilities for the amino-acid sequence of a protein to fit to known protein 3D structures using a structural alphabet, known as "Protein Blocks" (PBs). PBs constitute a library of 16 local structural prototypes that approximate every part of protein backbone structures. It is used to encode 3D protein structures into 1D PB sequences and to capture sequence to structure relationships. Our method relies on amino acid occurrence matrices, one for each PB, to score global and local threading of query amino acid sequences to protein folds encoded into PB sequences. It does not use any information from residue contacts or sequence-search methods or explicit incorporation of hydrophobic effect. The performance of the method was assessed with independent test datasets derived from SCOP 1.75A. With a Z-score cutoff that achieved 95% specificity (i.e., less than 5% false positives), global and local threading showed sensitivity of 64.1% and 34.2%, respectively. We further tested its performance on 57 difficult CASP10 targets that had no known homologs in PDB: 38 compatible templates were identified by our approach and 66% of these hits yielded correctly predicted structures. This method scales-up well and offers promising perspectives for structural annotations at genomic level. It has been implemented in the form of a web-server that is freely available at http://www.bo-protscience.fr/forsa. © 2014 The Protein Society.

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