Interplay between YAP/TAZ and metabolic dysfunction-associated steatotic liver disease progression. Archives of pharmacal research Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming an increasingly pressing global health challenge, with increasing mortality rates showing an upward trend. Two million deaths occur annually from cirrhosis and liver cancer together each year. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), key effectors of the Hippo signaling pathway, critically regulate tissue homeostasis and disease progression in the liver. While initial studies have shown that YAP expression is normally restricted to cholangiocytes in healthy livers, the activation of YAP/TAZ is observed in other hepatic cells during chronic liver disease. The disease-driven dysregulation of YAP/TAZ appears to be a critical element in the MASLD progression, contributing to hepatocyte dysfunction, inflammation, and fibrosis. In this study, we focused on the complex roles of YAP/TAZ in MASLD and explored how the YAP/TAZ dysregulation of YAP/TAZ drives steatosis, inflammation, fibrosis, and cirrhosis. Finally, the cell-type-specific functions of YAP/TAZ in different types of hepatic cells, such as hepatocytes, hepatic stellate cells, hepatic macrophages, and biliary epithelial cells are discussed, highlighting the multifaceted impact of YAP/TAZ on liver physiology and pathology. 10.1007/s12272-024-01501-5

VGLL3 is a mechanosensitive protein that promotes cardiac fibrosis through liquid-liquid phase separation. Nature communications Myofibroblasts cause tissue fibrosis by producing extracellular matrix proteins, such as collagens. Humoral factors like TGF-β, and matrix stiffness are important for collagen production by myofibroblasts. However, the molecular mechanisms regulating their ability to produce collagen remain poorly characterised. Here, we show that vestigial-like family member 3 (VGLL3) is specifically expressed in myofibroblasts from mouse and human fibrotic hearts and promotes collagen production. Further, substrate stiffness triggers VGLL3 translocation into the nucleus through the integrin β1-Rho-actin pathway. In the nucleus, VGLL3 undergoes liquid-liquid phase separation via its low-complexity domain and is incorporated into non-paraspeckle NONO condensates containing EWS RNA-binding protein 1 (EWSR1). VGLL3 binds EWSR1 and suppresses miR-29b, which targets collagen mRNA. Consistently, cardiac fibrosis after myocardial infarction is significantly attenuated in Vgll3-deficient mice, with increased miR-29b expression. Overall, our results reveal an unrecognised VGLL3-mediated pathway that controls myofibroblasts' collagen production, representing a novel therapeutic target for tissue fibrosis. 10.1038/s41467-023-36189-6

Phase separation drives the folding of recombinant collagen. International journal of biological macromolecules Recombinantly produced collagens present a sustainable, ethical, and safe substitute for collagens derived from natural sources. However, controlling the folding of the recombinant collagens, crucial for replicating the mechanical properties of natural materials, remains a formidable task. Collagen-like proteins from willow sawfly are relatively small and contain no hydroxyprolines, presenting an attractive alternative to the large and post-translationally modified mammalian collagens. Utilizing CD spectroscopy and analytical ultracentrifugation, we demonstrate that recombinant willow sawfly collagen assembles into collagen triple helices in a concentration-dependent manner. Interestingly, we observed that the lower concentration threshold for the folding can be overcome by freezing or adding crowding agents. Microscopy data show that both freezing and the addition of crowding agents induce phase separation. We propose that the increase in local protein concentration during phase separation drives the nucleation-step of collagen folding. Finally, we show that freezing also induces the folding of recombinant human collagen fragments and accelerates the folding of natural bovine collagen, indicating the potential to apply phase separation as a universal mechanism to control the folding of recombinant collagens. We anticipate that the results provide a method to induce the nucleation of collagen folding without any requirements for genetic engineering or crosslinking. 10.1016/j.ijbiomac.2024.137170