The Hippo kinase LATS2 impairs pancreatic ß-cell survival in diabetes through the mTORC1-autophagy axis.

Diabetes results from a decline in functional pancreatic ß-cells, but the molecular mechanisms underlying the pathological ß-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces ß-cell apoptosis and impaired function. LATS2 deficiency in ß-cells and primary isolated human islets as well as ß-cell specific LATS2 ablation in mice improves ß-cell viability, insulin secretion and ß-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in ß-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates ß-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating ß-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic ß-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic ß-cell survival and function in diabetes.

Janus nanoparticles designed for extended cell surface attachment.

In this study, we present Janus nanoparticles that are designed for attaching to a eukaryotic cell surface with minimal cell uptake. This contrasts the rapid uptake via various endocytosis pathways that non-passivated isotropic particles usually encounter. Firmly attaching nanoparticles onto cell surfaces for extended periods of time can be a powerful new strategy to employ functional properties of nanoparticles for non-invasive interrogation and manipulation of biological systems. To this end, we synthesized rhodamine-doped silica (SiO2) nanoparticles functionalized with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) on one hemisphere of the nanoparticle surface and high-molecular-weight long-chain poly(ethylene glycol) on the other one using the wax-Pickering emulsion technique. Nanoparticle localization was studied with NIH 3T3 rat fibroblasts in vitro. In these studies, the Janus nanoparticles adhered to the cell surface and, in contrast to isotropic control particles, only negligible uptake into the cells was observed, even after 24 h of incubation. In order to characterize the potential endocytosis pathway involved in the uptake of the Janus nanoparticles in more detail, fibroblasts and nanoparticles were incubated in the presence or absence of different endocytosis inhibitors. Our findings indicate that the Janus particles are not affected by caveolae- and receptor-mediated endocytosis and the prolonged attachment of the Janus nanoparticles is most likely the result of an incomplete macropinocytosis process. Consequently, by design, these Janus nanoparticles have the potential to firmly anchor onto cell surfaces for extended periods of time and might be utilized in various biotechnological and biomedical applications like cell surface tagging, magnetic manipulation of the cell membrane or non-invasive drug and gene delivery.