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g. Osterix/SP7 and IBSP). A combination of BMP2 (300 ng local) and GSK126 (5 μg local and 5 days of 50 mg/kg systemic) yielded more consistent bone healing than single treatments with either compound in a mouse calvarial critical-sized defect model according to results from μCT, histomorphometry, and surgical grading of qualitative X-rays. We conclude that EZH2 inhibition facilitates BMP2-mediated induction of osteogenic differentiation of progenitor cells and maturation of committed osteoblasts. We propose that epigenetic priming, coupled with bone anabolic agents, enhances osteogenesis and could be leveraged in therapeutic strategies to improve bone mass. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Members of the interleukin (IL)-1 family are key determinants of inflammation. Despite their role as intercellular mediators, most lack the leader peptide typically required for protein secretion. This lack is a characteristic of dozens of other proteins that are actively and selectively secreted from living cells independently of the classical endoplasmic reticulum-Golgi exocytic route. These proteins, termed leaderless secretory proteins (LLSPs), comprise proteins directly or indirectly involved in inflammation, including cytokines such as IL-1β and IL-18, growth factors such as fibroblast growth factor 2 (FGF2), redox enzymes such as thioredoxin, and proteins most expressed in the brain, some of which participate to the pathogenesis of neurodegenerative disorders. In spite of much effort, motifs that promote LLSP secretion remain to be identified. In this review, we summarize the mechanisms and pathophysiological significance of the unconventional secretory pathways that cells use to release LLSPs. We place special emphasis on redox regulation and inflammation, with focus on IL-1β, which is secreted after processing of its biologically inactive precursor pro-IL-1β in the cytosol. Although LLSP externalization remains poorly understood, some possible mechanisms have emerged. For example, a common feature of LLSP pathways is that they become active in response to stress and that they involve several distinct excretion mechanisms, including direct plasma membrane translocation, lysosome exocytosis, exosome formation, membrane vesiculation, autophagy, and pyroptosis. Further investigations of unconventional secretory pathways for LLSP secretion may shed light on their evolution and could help advance therapeutic avenues for managing pathological conditions such as diseases arising from inflammation. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Mitochondrial dysfunction is implicated in sporadic and familial Parkinson's disease (PD). However, the mechanisms that impair homeostatic responses to mitochondrial dysfunction remain unclear. Previously, we found that chronic, low dose administration of the mitochondrial complex I inhibitor 1-methyl-4-phenylpyridinium (MPP+) dysregulates mitochondrial fission-fusion, mitophagy and mitochondrial biogenesis. Given that PTEN-induced kinase 1 (PINK1) regulates mitochondrial function, dynamics and turnover, we hypothesized that alterations in endogenous PINK1 levels contribute to depletion of mitochondria during chronic complex I injury. Here we found that chronic MPP+ treatment of differentiated SH-SY5Y neuronal cells significantly decreases PINK1 expression prior to reductions in other mitochondrial components. Furthermore, Bcl2 associated athanogene 6 (BAG6, BAT3, or Scythe), a protein involved in protein quality control and degradation, was highly up-regulated during the chronic MPP+ treatment. BAG6 interacted with PINK1, and BAG6 overexpression decreased the half-life of PINK1. Salinomycin order Conversely, siRNA-mediated BAG6 knockdown prevented chronic MPP+ stress-induced loss of PINK1, reversed MPP+-provoked mitochondrial changes, increased cell viability and prevented MPP+-induced dendrite shrinkage in primary neurons. These results indicate that BAG6 up-regulation during chronic complex I inhibition contributes to mitochondrial pathology by decreasing the levels of endogenous PINK1. Given that recessive mutations in PINK1 cause familial PD, the finding of accelerated PINK1 degradation in the chronic MPP+ model suggests that PINK1 loss-of-function represents a point of convergence between neurotoxic and genetic causes of PD. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Lysine N-pyrrolation converts lysine residues to N ε-pyrrole-L-lysine (pyrK) in a covalent modification reaction that significantly affects the chemical properties of proteins causing them to mimic DNA. pyrK in proteins has been detected in vivo, indicating that the pyrrolation occurs as an endogenous reaction. However, the source of pyrK remains unknown. In this study, on the basis of our observation in vitro that pyrK is present in oxidized low-density lipoprotein and in modified proteins with oxidized polyunsaturated fatty acids, we used LC-electrospray ionization (ESI)-MS/MS coupled with a stable isotope dilution method to perform activity-guided separation of active molecules in oxidized lipids and identified glycolaldehyde (GA) as a pyrK source. Results from mechanistic experiments to study GA-mediated lysine N-pyrrolation suggested that the reactions might include GA oxidation, generating the dialdehyde glyoxal, followed by condensation reactions of lysine amino groups with GA and glyoxal. We also studied the functional significance of the GA-mediated lysine N-pyrrolation in proteins and found that the GA-modified proteins are recognized by apolipoprotein E, a binding target of pyrrolated proteins. Moreover, the GA-modified proteins triggered an immune response to the pyrrolated proteins, and the monoclonal antibodies generated from mice immunized with the GA-modified proteins specifically recognized the pyrrolated proteins. These findings reveal that GA is an endogenous source of DNA-mimicking pyrrolated proteins and may provide mechanistic insights relevant for innate and autoimmune responses associated with glucose metabolism and oxidative stress. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.