La communication entre le récepteur de l`insuline et la class III de la
Transcription
La communication entre le récepteur de l`insuline et la class III de la
La communication entre le récepteur de l’insuline et la class III de la PI3K – des mots doux pour le foie La communication est la propriété fondamentale de la vie. Elle intervient à tous les niveaux pour assurer que les processus biologiques sont ajustés pour s’adapter aux changements permanents de l’environnement. Un des centres de communication essentiels dans le contrôle des processus anaboliques et cataboliques est la voie de signalisation du récepteur de l’insuline (IR). Les études fondamentales ont démontré le rôle clé de la signalisation par IR dans le foie pour le métabolisme du glucose. De plus, il est plus en plus reconnu que le système endo/lysosomale contrôle la signalisation de récepteurs membranaires y compris de l’IR. L'équipe dirigée par Mario Pende à l’Institut Necker-Enfants malades - centre de médecine moléculaire - s’est demandé comment le trafic et la signalisation de l'IR sont coordonnés dans les hépatocytes. Dans leur travail précédant, l'équipe de M. Pende a démontré que la PI3K de classe III (PI3K-III), un complexe enzymatique présent dans chaque cellule eucaryote de la levure aux mammifères, est indispensable pour l'homéostasie du tissu musculaire en régulant l'activité lysosomale et le flux autophagique. Le travail actuel de l'équipe a fourni la preuve que dans les hépatocytes la PI3K-III coordonne les réponses á l'insuline par la régulation du trafic intracellulaire de l’IR. Leur analyse de mutants hépatiques de Vps15, la sous-unité régulatrice du complexe PI3K-III, a révélé son rôle crucial dans la régulation négative de l’IR assurant l'homéostasie du glucose in vivo. Suivant cette ligne, ils ont découvert les mécanismes moléculaires par lesquels l'insuline peut inhiber puissamment l’autophagie et en même temps stimuler l'absorption des nutriments, les deux processus contrôlés par la PI3K-III. L'étude a été complétée par des observations que la perte de la PI3K-III améliore la signalisation de l’insuline et améliore le syndrome métabolique dans des modèles animaux de diabète. Ainsi, les auteurs ont proposé que la PI3K-III puisse représenter une cible thérapeutique potentielle dans des conditions métaboliques de résistance à l'insuline. En résumé, le rapport de Ivan Nemazanyy et al. a découvert la relation inconnue de la PI3K-III et la signalisation IR dans le contrôle du métabolisme hépatique. A dialogue of Insulin receptor and class III PI3K - sweet words to liver Communication is the fundamental property of life. It could be as enjoyable as hot round-table discussions in the institute canteen on the latest trends in a labcoat fashion. Less obvious but equally important, it is happening on every level to assure that biological processes are fine-tuned to adapt to ever changing environmental cues. One of the critical communication hubs in the control of anabolic and catabolic processes is insulin receptor/Akt signalling (IR/Akt). Seminal studies have provided the evidence on the key role of hepatic IR/Akt transduction for glucose metabolism. Importantly, it is becoming more and more appreciated that a complex endo/lysosomal trafficking system functions in the cell to coordinate nutrient sensing, nutrient uptake and metabolism but equally important it controls signalling outputs from the membrane receptors. How it is happening, what are the molecular mechanisms behind those processes and what are the bigger implications to human pathology – the answers to those questions are just starting to emerge. The team directed by Mario Pende at INEM INSERM U1151 asked how trafficking and insulin signalling are coordinated in hepatocytes. They focussed on class III PI3K, the evolutionary conserved enzyme complex present in every eukaryotic cell from yeast to mammals. Class III PI3K plays a central role in coordinating endocytosis and autophagy, two fundamental pathways to acquire nutrients in time of plenty or starvation. In their previous work, M. Pende team has demonstrated that class III PI3K is an essential gene product and its activity is indispensable for muscle tissue homeostasis by regulating lysosomal activity and autophagic flux. To date, no studies addressed the molecular interactions between IR and class III PI3K in vivo. The current work of the team provided the evidence that class III PI3K coordinates insulin responses through regulation of IR intracellular trafficking. Their analysis of hepatic mutants of Vps15, the regulatory subunit in class III PI3K complex, revealed its critical role in IR downregulation ensuring glucose homeostasis in vivo. Following this line, they discovered the molecular mechanisms of how insulin can potently inhibit autophagy but at the same time stimulate nutrient uptake, both processes controlled by class III PI3K. Nemazanyy and colleagues have shown that insulin stimulated uniquely UVRAG-associated class III PI3K activity representing a novel mechanism of IR signalling retro-control. The study was completed by observations that loss of class III PI3K ameliorated IR signalling and relieved the metabolic syndrome in animal models of diabetes. Thus, the authors proposed that feedback regulation of IR trafficking and function by class III PI3K may represent a potential therapeutic target in metabolic conditions of insulin resistance. The compounds which target class III PI3K which were recently developed by Astra Zeneca, Sanofi and Novartis pharmaceutical giants could be instrumental to test this hypothesis in future. Equally important, this work prompts a critical evaluation of whether the autophagy block is sufficient to drive hepatic insulin resistance and reveals a complexity of class III PI3K function in mammals. The work of I. Nemazanyy and colleagues contributes to a rapidly evolving field of endo/lysosomal trafficking in signalling and metabolism control. Recent report from the team of M. Zerial demonstrated that interference with the endosomal system in the liver results in severe metabolic perturbations including decrease in the expression of enzymes controlling de novo glucose production. Furthermore, a study by Naguib A. et al. in Molecular Cell suggested that PI3P-positive endosomes act as a subcellular compartment important for Akt signalling regulation via recruitment of PTEN, a lipid phosphatase and suppressor in the insulin signalling pathway. Finally, very recent work from D. Sabatini team provided the evidence that dysregulated endomembrane trafficking might have oncogenic potential by activating PI3K/Akt signalling. In summary, the report by Ivan Nemazanyy et al. provides for the first time the molecular evidence of the unappreciated crosstalk of class III PI3K and IR signalling in hepatic metabolism control. The future work will address the molecular network downstream of class III PI3K and its role in norm and in disease…. more talks in canteen to follow. Reference: http://www.nature.com/ncomms/2015/150921/ncomms9283/full/ncomms9283.html Figure legend: Schematic representation of the crosstalk between class III PI3K and insulin receptor signalling. In hepatocytes, insulin activates class III PI3K lipid kinase activity exclusively in UVRAGcontaining complexes. Whereas, loss of class III PI3K delays insulin receptor degradation and prologue signal transduction from the endosomal compartment. th Support: This work was supported by grants from the European Research Council, the European 7 Framework MyoAge program, from Fondation de la Recherche Medicale, from Fondation Schlumberger pour l’Education et la Recherche, from European Foundation for the Study of Diabetes, from Institut National du Cancer (INCa), from French Muscular Dystrophy Asscoiation (AFM). Ganna Panasyuk and Ivan Nemazanyy were supported by personal fellowships from Fondation Tourre and EMBO Short Term Fellowship, respectively. Online summary in ENGLISH: Class III PI3K regulates endocytosis, endosomal sorting and autophagy. The work directed by Ganna Panasyuk and Mario Pende at INEM INSERM U1151 discovered unappreciated interaction between two evolutionary conserved signalling pathways – insulin receptor signalling and class III PI3K. The scientists show for the first time that insulin activates selective class III PI3K complex. In turn, class III PI3K promotes insulin receptor endocytic trafficking and lysosomal degradation, providing negative feedback by reducing the time it is activated. The work opens new avenues to novel treatment of metabolic disorders with insulin resistance by modulating class III PI3K signalling. Contact chercheurs : Ganna Panasyuk et Mario Pende Equipe Contrôle de la croissance cellulaire par les nutriments Inserm U1151/CNRS UMR 8253 Institut Necker Enfants Malades Institute [email protected] - [email protected] Tél. : 01 72 60 63 87 / 01 72 60 63 86