Growing evidences suggest that the fibroblast growth factor/FGF receptor (FGF/FGFR) signaling has crucial roles in a multitude of processes during embryonic development and adult homeostasis by regulating cellular lineage commitment, differentiation, proliferation, and apoptosis of various types of cells. In this review, we provide a comprehensive overview of the current understanding of FGF signaling and its roles in organ development, injury repair, and the pathophysiology of spectrum of diseases, which is a consequence of FGF signaling dysregulation, including cancers and chronic kidney disease (CKD). In this context, the agonists and antagonists for FGF-FGFRs might have therapeutic benefits in multiple systems.

Synovitis, a common clinical symptom for osteoarthritis (OA) patients, is highly related to OA pathological progression and pain manifestation. The activated synovial macrophages have been demonstrated to play an important role in synovitis, but the mechanisms about macrophage activation are still not clear. In this study, we found that the exosome-like vesicles from osteoarthritic chondrocytes could be a new biological factor to stimulate inflammasome activation and increase mature IL-1β production in macrophages. The degraded cartilage explants produced more exosome-like vesicles than the nondegraded ones, while the exosome-like vesicles from chondrocytes could enter into joint synovium tissue and macrophages. Moreover, the exosome-like vesicles from osteoarthritic chondrocytes enhanced the production of mature IL-1β in macrophages. These vesicles could inhibit ATG4B expression via miR-449a-5p, leading to inhibition of autophagy in LPS-primed macrophages. The decreased autophagy promoted the production of mitoROS, which further enhanced the inflammasome activation and subsequent IL-1β processing. Ultimately, the increase of mature IL-1β may aggravate synovial inflammation and promote the progression of OA disease. Our study provides a new perspective to understand the activation of synovial macrophages and synovitis in OA patients, which may be beneficial for therapeutic intervention in synovitis-related OA patients.

The Sec translocon is a central component of cellular pathways for protein translocation and membrane integration. Using both atomistic and coarse-grained molecular simulations, we investigate the conformational landscape of the translocon and explore the role of peptide substrates in the regulation of the translocation and integration pathways. Inclusion of a hydrophobic peptide substrate in the translocon stabilizes the opening of the lateral gate for membrane integration, whereas a hydrophilic peptide substrate favors the closed lateral gate conformation. The relative orientation of the plug moiety and a peptide substrate within the translocon channel is similarly dependent on whether the substrate is hydrophobic or hydrophilic in character, and the energetics of the translocon lateral gate opening in the presence of a peptide substrate is governed by the energetics of the peptide interface with the membrane. Implications of these results for the regulation of Sec-mediated pathways for protein translocation vs. membrane integration are discussed.coarse graining | free-energy landscape | hydrophobicity | membrane integration | protein translocation A critical step in the biosynthesis of many proteins involves either translocation of the protein across a cellular membrane or integration into the membrane (1, 2). Both proceed via the Sec translocon-a ubiquitous and highly conserved transmembrane channel (3-5). Using atomistic and coarse-grained (CG) simulations and free-energy calculations, it is demonstrated that hydrophobic peptide substrates stabilize large-scale conformational changes in the translocon. The energetics of this conformational gating is dominated by the substrate-membrane interface, suggesting a regulatory mechanism for the Secfacilitated protein translocation and integration pathways in which the translocon acts as a conformational switch under the control of the peptide substrate.The Sec translocon is a heterotrimeric complex of membranebound proteins that forms a passive channel for posttranslational and cotranslational protein translocation, as well as the cotranslational integration of proteins into the phospholipid bilayer (6). Structural (7-11), biochemical (12, 13), and genetic (14) studies indicate that the translocon undergoes large-scale conformational changes during both the translocation and integration pathways. The translocon channel exhibits a ring, or pore, of hydrophobic amino acid residues, as well as an α-helical plug moiety that rests against the pore to occlude the channel; secretion of protein domains via the translocation pathway requires displacement of the plug with respect to the pore (Fig. 1, Left) (8, 12, 14). A pair of transmembrane helices in the translocon forms a lateral gate (LG) that opens to expose the interior of the channel to the membrane bilayer (Fig. 1, Right) and facilitates membrane integration (13,15,16).The interaction between the peptide and the membrane lipid is recognized to play an important role in directing the integration of transmembrane heli...