Mechanical forces regulate multiple essential pathways in the cell. The nuclear translocation of mechanoresponsive transcriptional regulators is an essential step for mechanotransduction. However, how mechanical forces regulate the nuclear import process is not understood. Here, we identify a highly mechanoresponsive nuclear transport receptor (NTR), Importin-7 (Imp7), that drives the nuclear import of YAP, a key regulator of mechanotransduction pathways. Unexpectedly, YAP governs the mechanoresponse of Imp7 by forming a YAP/Imp7 complex that responds to mechanical cues through the Hippo kinases MST1/2. Furthermore, YAP behaves as a dominant cargo of Imp7, restricting the Imp7 binding and the nuclear translocation of other Imp7 cargoes such as Smad3 and Erk2. Thus, the nuclear import process is an additional regulatory layer indirectly regulated by mechanical cues, which activate a preferential Imp7 cargo, YAP, which competes out other cargoes, resulting in signaling crosstalk.
The plasma membrane (PM) is subjected to multiple mechanical forces, and it must adapt and respond to them. PM invaginations named caveolae, with a specific protein and lipid composition, play a crucial role in this mechanosensing and mechanotransduction process. They respond to PM tension changes by flattening, contributing to the buffering of high-range increases in mechanical tension, while novel structures termed dolines, sharing Caveolin1 as the main component, gradually respond to low and medium forces. Caveolae are associated with different types of cytoskeletal filaments, which regulate membrane tension and also initiate multiple mechanotransduction pathways. Caveolar components sense the mechanical properties of the substrate and orchestrate responses that modify the extracellular matrix (ECM) according to these stimuli. They perform this function through both physical remodeling of ECM, where the actin cytoskeleton is a central player, and via the chemical alteration of the ECM composition by exosome deposition. Here, we review mechanotransduction regulation mediated by caveolae and caveolar components, focusing on how mechanical cues are transmitted through the cellular cytoskeleton and how caveolae respond and remodel the ECM.
Introduction: The interplay between mechanical stress and cell metabolism is an emerging topic. However, the mechanotransduction pathways coordinating cell metabolism to the tensional status of the cell are poorly understood. Here, we provide several evidences suggesting that caveolae – mechanosensitive plasma membrane invaginations-, nutrient availability and cell tension controlling conditions are important for the biology of mitochondrial ATP synthase. Material and Methods: For achieving the caveolar interactome, plasma membrane biotinylation and co-localization experiments, we have used human retinal pigment epithelial-1 (RPE-1) cells, murine vascular aortic smooth muscle (MOVAS) cells and mouse embryonic fibroblasts (MEF). We used proximity-dependent biotin identification (BioID) and mass spectrometry to obtain the different interactomes of caveolar components. For plasma membrane (PM) localization of the ATP synthase we used PM biotinylation under different metabolic and mechanical conditions (nutrient starving, cell confluence). To study co-localization, we performed Proximity Ligation Assays (PLAs) in combination with mitochondrial and caveolar markers. Results: First, we have identified the interactome of all core caveolar components. Among the interactors, we identified subunits α and β of the mitochondrial ATP synthase, which interact with most of the caveolar components. Apart from its main localization at the inner mitochondrial membrane, the ATP synthase has also been detected in the PM, facing the extracellular space; this pool is known as ecto-ATP synthase. We show that the interaction with Caveolin-1 (Cav1), one of the main components of caveolae, occurs outside caveolae and mitochondria. In addition, the presence of ecto- ATP synthase at the PM is dependent on Cav1. Furthermore, conditions regulating cell tension, and metabolic challenges that promote autophagy, impinge on ecto-ATP synthase trafficking Conclusions: This study has characterized the interactome of caveolar components and has focused on the subunits α and β of the ATP synthase, which are also present at the PM. These subunits interact with Cav-1, but this interaction seems to occur in intracellular trafficking vesicles. Moreover, this process could be altered by mechanical cues and nutrient deprivation. Thus, our study suggests that trafficking routes regulating PM residents, and regulated by several caveolar components, are linked to nutrient starvation and mitochondrial biology.
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