12 research outputs found
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-ÎșB, 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-ÎșB 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
LâimmunitĂ© innĂ©e reprĂ©sente la premiĂšre ligne de dĂ©fense dâun organisme face Ă une infection virale, en engendrant une rĂ©ponse rapide capable de restreindre la menace microbienne. Dans la cellule, les rĂ©cepteurs Toll-likes (TLRs) et les hĂ©licases cytosoliques RIG-I like (RLRs) reprĂ©sentent les deux systĂšmes majeurs de reconnaissance des virus. Les acides nuclĂ©iques viraux sont notamment reconnus les hĂ©licases cytosoliques RIG-I et MDA5. Ces deux protĂ©ines possĂšdent deux domaines CARD impliquĂ©s dans le recrutement de la protĂ©ine adaptatrice MAVS, capable dâinduire lâactivation des promoteurs interfĂ©rons (IFNs) de type I et de NF-B pour la mise en place dâune rĂ©ponse antivirale. De façon surprenante, MAVS est localisĂ©e au niveau de la mitochondrie et a besoin de cette association au compartiment mitochondrial pour exercer sa fonction. Bien que de nombreuses Ă©tudes aient montrĂ© le rĂŽle crucial de la protĂ©ine mitochondriale MAVS dans la signalisation antivirale des RLRs, sa rĂ©gulation est encore mal connue Ă ce jour. Ce travail de doctorat a permis de mettre en Ă©vidence que la dĂ©gradation de MAVS suite Ă une infection virale est nĂ©cessaire Ă la transduction du signal antiviral. Nous avons ainsi dĂ©terminĂ© que lâE3 ubiquitine ligase TRIM25 induit lâubiquitination puis la dĂ©gradation de MAVS quelques heures aprĂšs une infection virale. De plus, nous avons montrĂ© que lâactivation du signalosome aboutissant Ă la production des IFNs de type I et dĂ©pendant de MAVS nâa lieu que suite Ă sa translocation de la mitochondrie vers le cytosol permise par la dĂ©gradation de MAVS. Enfin, nous avons mis en Ă©vidence le rĂŽle essentiel de lâĂ©longation du rĂ©seau mitochondrial suite Ă une infection virale pour la transduction du signal dĂ©pendant 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
Lâutilisation de lâenseignement mutuel au sein dâune classe de 1re ST2S en Biologie et Physiopathologie Humaines peut-elle apporter un bĂ©nĂ©fice pour la mise en activitĂ© et lâimplication des Ă©lĂšves ?
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 pupilsâ 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 pupilsâmotivation 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 pupilsâ feeling of motivation and usefulness. When evaluating posture, participation and written record, we also noted a significant benefit of our scheme. Considering Maslowâs 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 dĂ©roulement dâun cours, la mise en activitĂ© et lâimplication des Ă©lĂšves dans une tĂąche peut ĂȘtre problĂ©matique. Nous avons recherchĂ© des clĂ©s pĂ©dagogiques permettant dâaugmenter la motivation des Ă©lĂšves et donc leur mise au travail. Nous avons comparĂ© 2 mĂ©thodes : la mĂ©thode « simultanĂ©e », oĂč lâenseignant dispense le savoir de maniĂšre verticale et la mĂ©thode « mutuelle », oĂč des Ă©lĂšves « moniteurs » dirigent lâacquisition des connaissances par leurs camarades. Nous formulons lâhypothĂšse que lâenseignement mutuel dans une classe de 1re ST2S en Biologie et Physiopathologie Humaines pourrait favoriser lâimplication et la motivation des Ă©lĂšves lors dâune activitĂ©. Lorsque nous comparons classe TĂ©moin (mĂ©thode simultanĂ©e) et Test (mĂ©thode mutuelle) nous observons un effet positif significatif de la mise en place dâune classe mutuelle sur la motivation et la valorisation des Ă©lĂšves. LâĂ©valuation de la posture, la participation et la qualitĂ© de la trace Ă©crite rĂ©vĂšle Ă©galement un bĂ©nĂ©fice significatif du dispositif. Nous pensons que les diffĂ©rences de comportement observĂ©es entre la classe Test et de la classe TĂ©moin sont la consĂ©quence de la (in)complĂ©tude de pyramide des besoins de Maslow. Le dispositif de classe mutuelle remplissant cette pyramide pourrait motiver les Ă©lĂšves et donc favoriser leur mise au travail. Ă lâavenir, Il serait intĂ©ressant de comparer lâinfluence de la mĂ©thode pĂ©dagogique utilisĂ©e sur la rĂ©tention dâinformations par les Ă©lĂšves
La dynamique mitochondriale au cours de lâapoptose
Les mitochondries se prĂ©sentent sous la forme dâun rĂ©seau dynamique dont la morphologie rĂ©sulte dâun Ă©quilibre entre des Ă©vĂšnements de fusion et de fission de lâorganite. Lors de lâapoptose, il se produit une fragmentation du rĂ©seau mitochondrial et un remodelage des crĂȘtes de la membrane interne. Lâimpact de cette fragmentation des mitochondries sur lâapoptose est lâobjet dâun dĂ©bat. En effet, certains proposent que cette fragmentation des mitochondries est importante pour lâexĂ©cution de lâapoptose alors que dâautres suggĂšrent quâil ne sâagit que dâune consĂ©quence du processus apoptotique. Dans cette revue, nous discuterons les mĂ©canismes molĂ©culaires qui contrĂŽlent la morphologie mitochondriale au cours de lâapoptose
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 (Ï), 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 mitochondriaâER 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 VÎł9VÎŽ2 T cells based-immunotherapy in pancreatic ductal adenocarcinoma (PDAC)
International audienc