Sun-mediated mechanical LINC between nucleus and cytoskeleton regulates beta catenin nuclear access

摘要

beta catenin acts as a primary intracellular signal transducer for mechanical and Wnt signaling pathways to control cell function and fate. Regulation of beta catenin in the cytoplasm has been well studied but beta catenin nuclear trafficking and function remains unclear. In a previous study we showed that, in mesenchymal stem cells (MSC), mechanical blockade of adipogenesis relied on inhibition of beta catenin destruction complex element GSK3 beta (glycogen synthase kinase 313) to increase nuclear beta catenin as well as the function of Linker of Cytoskeleton and Nucleoskeleton (LINC) complexes, suggesting that these two mechanisms may be linked. Here we show that shortly after inactivation of GSK3 beta due to either low intensity vibration (LIV), substrate strain or pharmacologic inhibition, beta catenin associates with the nucleoskeleton, defined as the insoluble nuclear fraction that provides structure to the integrated nuclear envelope, nuclear lamina and chromatin. Co-depleting LINC elements Sun-1 and Sun-2 interfered with both nucleoskeletal association and nuclear entry of beta catenin, resulting in decreased nuclear beta catenin levels. Our findings reveal that the insoluble structural nucleoskeleton actively participates in beta catenin dynamics. As the cytoskeleton transmits applied mechanical force to the nuclear surface to influence the nucleoskeleton and its LINC mediated interaction, our results suggest a pathway by which LINC mediated connectivity may play a role in signaling pathways that depend on nuclear access of beta catenin. (C) 2018 Elsevier Ltd. All rights reserved.