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.
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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