MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors

<p>Abstract</p> <p>Background</p> <p>During a viral infection, the intracellular RIG-I-like receptors (RLRs) sense viral RNA and signal through the mitochondrial antiviral signaling adaptor MAVS (also known as IPS-1, Cardif and VISA) whose activation triggers a rapid production of type I interferons (IFN) and of pro-inflammatory cytokines through the transcription factors IRF3/IRF7 and NF-κB, respectively. While MAVS is essential for this signaling and known to operate through the scaffold protein NEMO and the protein kinase TBK1 that phosphorylates IRF3, its mechanism of action and regulation remain unclear.</p> <p>Results</p> <p>We report here that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling. Inhibition of this MAVS degradation with a proteasome inhibitor does not affect NF-κB signaling but it hampers IRF3 activation, and NEMO and TBK1, two essential mediators in type I IFN production, are retained at the mitochondria.</p> <p>Conclusions</p> <p>These results suggest that MAVS functions as a recruitment platform that assembles a signaling complex involving NEMO and TBK1, and that the proteasome-mediated MAVS degradation is required to release the signaling complex into the cytosol, allowing IRF3 phosphorylation by TBK1.</p

Study of the regulation of MAVS, a mitochondrial protein involves in antiviral innate immunity

L’immunité innée représente la première ligne de défense d’un organisme face à une infection virale, en engendrant une réponse rapide capable de restreindre la menace microbienne. Dans la cellule, les récepteurs Toll-likes (TLRs) et les hélicases cytosoliques RIG-I like (RLRs) représentent les deux systèmes majeurs de reconnaissance des virus. Les acides nucléiques viraux sont notamment reconnus les hélicases cytosoliques RIG-I et MDA5. Ces deux protéines possèdent deux domaines CARD impliqués dans le recrutement de la protéine adaptatrice MAVS, capable d’induire l’activation des promoteurs interférons (IFNs) de type I et de NF-B pour la mise en place d’une réponse antivirale. De façon surprenante, MAVS est localisée au niveau de la mitochondrie et a besoin de cette association au compartiment mitochondrial pour exercer sa fonction. Bien que de nombreuses études aient montré le rôle crucial de la protéine mitochondriale MAVS dans la signalisation antivirale des RLRs, sa régulation est encore mal connue à ce jour. Ce travail de doctorat a permis de mettre en évidence que la dégradation de MAVS suite à une infection virale est nécessaire à la transduction du signal antiviral. Nous avons ainsi déterminé que l’E3 ubiquitine ligase TRIM25 induit l’ubiquitination puis la dégradation de MAVS quelques heures après une infection virale. De plus, nous avons montré que l’activation du signalosome aboutissant à la production des IFNs de type I et dépendant de MAVS n’a lieu que suite à sa translocation de la mitochondrie vers le cytosol permise par la dégradation de MAVS. Enfin, nous avons mis en évidence le rôle essentiel de l’élongation du réseau mitochondrial suite à une infection virale pour la transduction du signal dépendant de MAVS.Innate Immunity acts as the first line of the host defense against viral infection, providing a rapid response to restrict the microbial threats. Toll-like receptors (TLRs) and cytosolic RIG-I-like helicases (RLRs) are the two major receptor systems for detecting virus. Viral nucleic acids are recognised by the helicases RIG-I and MDA5. These receptors contain two CARD domains involve in the recruitment of the mitochondrial antiviral signaling adaptor MAVS whose activation triggers a rapid production of type 1 interferons (IFNs) and of pro-inflammatory cytokines. Interestingly, it has been reported that MAVS must be localized to mitochondria to exert its function. While MAVS is essential for this signaling, its function and regulation remain unclear. In this work, we report that RLR activation triggers MAVS ubiquitination by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling. MAVS appears to function as a recruitment platform to first assemble a signaling complex, then the proteasome-mediated MAVS degradation is required to unleash into the cytosol this signaling complex allowing the signalosome activation and ensuing type I IFNs production. Futhermore, we reported that mitochondrial dynamics regulate MAVS-mediated signaling after viral infection

L’utilisation de l’enseignement mutuel au sein d’une classe de 1re ST2S en Biologie et Physiopathologie Humaines peut-elle apporter un bénéfice pour la mise en activité et l’implication des élèves ?

A problematic task in the course of teaching often is to bring pupils to be actively involved in their work. We have looked for alternative pedagogy to enhance our pupils’ motivation and hence their involvment. We compared 2 methods : the classical "simultaneous" classroom, where a teacher vertically dispenses knowledge, and the "mutual" classroom, where each pupil acquires knowledge and becomes in turn mentor and mentee. Our hypothesis is that a mutual classroom could enhance pupils’motivation and involvment in a task. This hypothesis has been tested on 2nd year high school students in Human Biology and Physiopathology. When comparing a Control (simultaneous method) and Test (mutual method) group, we observe a significant positive effect of peer-mentoring on pupils’ feeling of motivation and usefulness. When evaluating posture, participation and written record, we also noted a significant benefit of our scheme. Considering Maslow’s pyramid of needs, we think that the differences in behaviours observed in the Test vs Control classes emerge from (un)completeness of this pyramid. The mutual classroom, by completing the pyramid, would motivate our students which in turn would improve their involvment in a designated task. In the future, it would be interesting to investigate the influence of a chosen pedagogy on retention of information.Dans le déroulement d’un cours, la mise en activité et l’implication des élèves dans une tâche peut être problématique. Nous avons recherché des clés pédagogiques permettant d’augmenter la motivation des élèves et donc leur mise au travail. Nous avons comparé 2 méthodes : la méthode « simultanée », où l’enseignant dispense le savoir de manière verticale et la méthode « mutuelle », où des élèves « moniteurs » dirigent l’acquisition des connaissances par leurs camarades. Nous formulons l’hypothèse que l’enseignement mutuel dans une classe de 1re ST2S en Biologie et Physiopathologie Humaines pourrait favoriser l’implication et la motivation des élèves lors d’une activité. Lorsque nous comparons classe Témoin (méthode simultanée) et Test (méthode mutuelle) nous observons un effet positif significatif de la mise en place d’une classe mutuelle sur la motivation et la valorisation des élèves. L’évaluation de la posture, la participation et la qualité de la trace écrite révèle également un bénéfice significatif du dispositif. Nous pensons que les différences de comportement observées entre la classe Test et de la classe Témoin sont la conséquence de la (in)complétude de pyramide des besoins de Maslow. Le dispositif de classe mutuelle remplissant cette pyramide pourrait motiver les élèves et donc favoriser leur mise au travail. À l’avenir, Il serait intéressant de comparer l’influence de la méthode pédagogique utilisée sur la rétention d’informations par les élèves

La dynamique mitochondriale au cours de l’apoptose

Les mitochondries se présentent sous la forme d’un réseau dynamique dont la morphologie résulte d’un équilibre entre des évènements de fusion et de fission de l’organite. Lors de l’apoptose, il se produit une fragmentation du réseau mitochondrial et un remodelage des crêtes de la membrane interne. L’impact de cette fragmentation des mitochondries sur l’apoptose est l’objet d’un débat. En effet, certains proposent que cette fragmentation des mitochondries est importante pour l’exécution de l’apoptose alors que d’autres suggèrent qu’il ne s’agit que d’une conséquence du processus apoptotique. Dans cette revue, nous discuterons les mécanismes moléculaires qui contrôlent la morphologie mitochondriale au cours de l’apoptose

Acceleration of MCNP calculations for small pipes configurations by using Weigth Windows Importance cards created by the SN-3D ATTILA

In the nuclear engineering, you have to manage time and precision. Especially in shielding design, you have to be more accurate and efficient to reduce cost (shielding thickness optimization), and for this, you use 3D codes. In this paper, we want to see if we can easily applicate the CADIS methods for design shielding of small pipes which go through large concrete walls. We assess the impact of the WW generated by the 3D-deterministic code ATTILA versus WW directly generated by MCNP (iterative and manual process). The comparison is based on the quality of the convergence (estimated relative error (σ), Variance of Variance (VOV) and Figure of Merit (FOM)), on time (computer time + modelling) and on the implement for the engineer

Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway

The intracellular retinoic acid-inducible gene I-like receptors (RLRs) sense viral ribonucleic acid and signal through the mitochondrial protein mitochondrial antiviral signalling (MAVS) to trigger the production of type I interferons and proinflammatory cytokines. In this study, we report that RLR activation promotes elongation of the mitochondrial network. Mimicking this elongation enhances signalling downstream from MAVS and favours the binding of MAVS to stimulator of interferon genes, an endoplasmic reticulum (ER) protein involved in the RLR pathway. By contrast, enforced mitochondrial fragmentation dampens signalling and reduces the association between both proteins. Our finding that MAVS is associated with a pool of mitofusin 1, a protein of the mitochondrial fusion machinery, suggests that MAVS is capable of regulating mitochondrial dynamics to facilitate the mitochondria–ER association required for signal transduction. Importantly, we observed that viral mitochondria-localized inhibitor of apoptosis, a cytomegalovirus (CMV) antiapoptotic protein that promotes mitochondrial fragmentation, inhibits signalling downstream from MAVS, suggesting a possible new immune modulation strategy of the CMV

Constitutive AKT activation in follicular lymphoma.

International audienceBackground:The phosphoinositide 3- kinase (PI3K) pathway is involved in the growth of various human cancers,including lymphoid malignancies. However its role in the pathogenesis of follicular lymphoma (FL) has not beenyet described.Methods:To clarify this point, biopsy tissue samples from 38 human FL cases were investigated for PIK3CA somaticmutations in exon 9 and 20 using direct sequencing. The same samples were analyzed using western blotting andimmunohistochemistry to detect expression of AKT, phosphorylated AKT (pAKT), and PTEN proteins. Two cases ofbenign lymphadenitis were used as controls.Results:AKT expression was present in all FL and lymphadenitis cases. 14/38 (37%) FL and 2/2 lymphadenitis casesexpressed pAKT. 9/38 (24%) FL samples showed high level of pAKT, whereas 5/38 (13%) FL cases and 2/2 benignlymphadenitis samples expressed low level of pAKT. PTEN expression was observed in 30/38 (79%) FL and 2/2benign lymphadenitis cases, whereas 8/38 (21%) FL cases showed loss of PTEN expression. 3 cases with positivepAKT did not express PTEN. PIK3CA mutations were not detected in any sample.Conclusions:These data suggest that the PI3K/AKT signaling pathway could be activated in a subset of FL cases,due to either AKT phosphorylation or PTEN downregulation, in the absence of PIK3CA mutations

BTN3A is a prognosis marker and a promising target for Vγ9Vδ2 T cells based-immunotherapy in pancreatic ductal adenocarcinoma (PDAC)

International audienc