EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription

Caveolae are small invaginated pits that function as dynamic mechanosensors to buffer tension variations at the plasma membrane. Here we show that under mechanical stress, the EHD2 ATPase is rapidly released from caveolae, SUMOylated, and translocated to the nucleus, where it regulates the transcription of several genes including those coding for caveolae constituents. We also found that EHD2 is required to maintain the caveolae reservoir at the plasma membrane during the variations of membrane tension induced by mechanical stress. Metal-replica electron microscopy of breast cancer cells lacking EHD2 revealed a complete absence of caveolae and a lack of gene regulation under mechanical stress. Expressing EHD2 was sufficient to restore both functions in these cells. Our findings therefore define EHD2 as a central player in mechanotransduction connecting the disassembly of the caveolae reservoir with the regulation of gene transcription under mechanical stress

Endocytose sans clathrine

L’intérêt porté à l’étude des mécanismes d’endocytose n’a jamais faibli tant ce phénomène tient une place essentielle dans le fonctionnement cellulaire. La croissance, l’adhésion et la différenciation cellulaires, la régulation de la signalisation induite par les récepteurs membranaires ou encore l’infection par des particules virales, dépendent toutes de l’entrée de molécules dans la cellule. Une fois l’endocytose dépendante de la clathrine bien caractérisée, il est apparu que d’autres processus d’entrée, qui ne mettent pas en jeu la clathrine, existent également dans la cellule. Cette synthèse a pour but de faire le point sur les avancées récentes qui établissent avec certitude l’existence des voies d’endocytose indépendantes de la clathrine, et qui mettent en évidence leurs régulations spécifiques

Receptor lipid nanodomain partitioning and signaling

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Interferon gamma receptor: The beginning of the journey

Our view of endocytosis and membrane trafficking of transmembrane receptors has dramatically changed over the last 20 years. Several new endocytic routes have been discovered and mechanistically characterized in mammalian cells. Long considered as a passive means to terminate signaling through down-regulation of the number of activated receptors at the plasma membrane, it is now established that receptor endocytosis and endosomal sorting can be directly linked to the regulation of intracellular signaling pathways. The functional links between membrane trafficking of interferon receptors and JAK/STAT signaling have recently begun to be unraveled. These studies raise the exciting possibility that a certain level of signal specificity can be achieved through endocytosis and selective localization of the activated complexes within cellular membranes. The ongoing development of high-resolution cell imaging techniques with better spatial and temporal resolution gives new means of deciphering the inherent complexity of membrane trafficking and signaling. This should help to better comprehend the molecular mechanisms by which endocytosis and endosomal sorting of interferon receptors can orchestrate signaling selectivity within the JAK/STAT pathway that can be activated by as many as 60 different cytokines, growth factors, and hormones

Dynamiques moléculaire et membranaire du récepteur de l’interféron gamma : pour un sucre de trop !

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Filling up adipocytes with lipids. Lessons from caveolin-1 deficiency

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STAM and Hrs interact sequentially with IFN-α Receptor to control spatiotemporal JAK–STAT endosomal activation

Activation of the JAK-STAT pathway by type I interferons (IFNs) requires clathrin-dependent endocytosis of the IFN-α and -β receptor (IFNAR), indicating a role for endosomal sorting in this process. The molecular machinery that brings the selective activation of IFN-α/β-induced JAK-STAT signalling on endosomes remains unknown. Here we show that the constitutive association of STAM with IFNAR1 and TYK2 kinase at the plasma membrane prevents TYK2 activation by type I IFNs. IFN-α-stimulated IFNAR endocytosis delivers the STAM-IFNAR complex to early endosomes where it interacts with Hrs, thereby relieving TYK2 inhibition by STAM and triggering signalling of IFNAR at the endosome. In contrast, when stimulated by IFN-β, IFNAR signalling occurs independently of Hrs as IFNAR is sorted to a distinct endosomal subdomain. Our results identify the molecular machinery that controls the spatiotemporal activation of IFNAR by IFN-α and establish the central role of endosomal sorting in the differential regulation of JAK-STAT signalling by IFN-α and IFN-β