Cardiac diseases are the leading cause of death. Available treatment approaches are not sufficient to reverse persistent cardiac damage after injury; thus, the search for new therapeutic targets is essential. Our microarray-based screening in rat hearts 24 h after myocardial infarction (MI) yielded glycoprotein nonmetastatic melanoma protein B (GPNMB), which is known to be involved in inflammation and fibrosis after tissue injury. However, its role in the heart was elusive. We found increased cardiac expression levels of GPNMB in rats and mice after MI. Analysis of DBA/2J mice, which lack functional GPNMB due to a spontaneous point mutation, showed that systemic GPNMB deficiency was associated with preserved cardiac function and less left ventricular dilation after MI compared with DBA/2J mice with reconstituted GPNMB expression. These improvements were associated with decreased expression of matrix metalloproteinase 9, the cardiac stress genes for natriuretic peptides (atrial natriuretic peptide and brain natriuretic peptide), and β-myosin heavy chain after MI. Moreover, GPNMB deficiency attenuated the dilated cardiomyopathy in muscle lim protein knockout mice but could not prevent cardiac hypertrophy induced by isoprenaline infusion. This is the first experimental study to show that GPNMB adversely influences myocardial remodeling.-Järve, A., Mühlstedt, S., Qadri, F., Nickl, B., Schulz, H., Hübner, N., Özcelik, C., Bader, M. Adverse left ventricular remodeling by glycoprotein nonmetastatic melanoma protein B in myocardial infarction.

Dynein light chain 8 (DLC8) is a ubiquitous eukaryotic protein regulating diverse cellular functions. We show that the obligate intracellular parasite Toxoplasma gondii harbors 4 DLC8 proteins (TgDLC8a-d), of which only TgDLC8a clusters in the mainstream LC8 class. TgDLC8b-d proteins form a divergent and alveolate-specific clade. TgDLC8b-d proteins are largely cytosolic, whereas TgDLC8a resides in the conoid at the apical end of T. gondii. The apical location of TgDLC8a is also not shared by its nearly identical Eimeria (EtDLC8a), Plasmodium (PfDLC8), or human (HsDLC8) orthologs. Notwithstanding an exclusive conoid targeting, TgDLC8a exhibits a classical LC8 structure. It forms a homodimer by swapping of the β strands that interact with the antiparallel β' strands of the opposing monomers. The TgDLC8a dimer contains two identical binding grooves and appears to be adapted for multitarget recognition. By contrast, the previously reported PfDLC8 homodimer is shaped by binding of the β strand with the parallel β' strand and lacks such a distinct binding interface. Our comparisons suggest an unexpected structural and functional divergence of the two otherwise conserved proteins from apicomplexan parasites. Finally, we demonstrate that a phosphomimetic S88E mutation renders the TgDLC8a-S88E mutant monomeric and cytosolic in T. gondii, and its overexpression inhibits the parasite growth in human fibroblasts.

Obesity can cause a chronic, low-grade inflammation, which is a critical step in the development of type II diabetes and cardiovascular diseases. Inflammation is associated with the expression of glycoprotein nonmetastatic melanoma protein b (Gpnmb), which is mainly expressed by macrophages and dendritic cells. We generated a Gpnmb-knockout mouse line using Crispr-Cas9 to assess the role of Gpnmb in a diet-induced obesity. The absence of Gpnmb did not affect body weight gain and blood lipid parameters. While wildtype animals became obese but remained otherwise metabolically healthy, Gpnmb-knockout animals developed, in addition to obesity, symptoms of metabolic syndrome such as adipose tissue inflammation, insulin resistance and liver fibrosis. We observed a strong Gpnmb expression in adipose tissue macrophages in wildtype animals and a decreased expression of most macrophage-related genes independent of their inflammatory function. This was corroborated by in vitro data showing that Gpnmb was mostly expressed by reparative macrophages while only pro-inflammatory stimuli induced shedding of Gpnmb. The data suggest that Gpnmb is ameliorating adipose tissue inflammation independent of the polarization of macrophages. Taken together, the data suggest an immune-balancing function of Gpnmb that could delay the metabolic damage caused by the induction of obesity.