The melanoma-associated transmembrane glycoprotein Gpnmb controls trafficking of cellular debris for degradation and is essential for tissue repair

Abstract

Kidney damage due to injury rarely resolves completely, and there are currently no therapies capable of promoting repair. In addition to understanding mechanisms by which tissues are damaged, illuminating mechanisms of repair and regeneration is also of great importance. Here we show that the melanoma-associated, transmembrane glycoprotein, Gpnmb, is up-regulated 15-fold following ischemic damage in kidney tissue and by more than 10-fold in macrophages and 3-fold in surviving epithelial cells. Gpnmb-expressing macrophages and epithelial cells were found to contain apoptotic bodies at 3 times the rate of nonexpressing cells. Either mutation of Gpnmb or ablation of inflammatory macrophages prevents normal repair of the kidney. Significantly, the kidneys from postischemic Gpnmb mutant mice exhibited a 5-fold increase in apoptotic cellular debris compared to wild-type mice. These mice also experienced an 85% increase in mortality following bilateral ischemic kidney. Finally, we demonstrate that Gpnmb is a phagocytic protein that is necessary for recruitment of the autophagy protein LC3 to the phagosome where these proteins are colocalized and for lysosomal fusion with the phagosome and hence bulk degradation of their content. Therefore, Gpnmb is a novel prorepair gene that is necessary for crosstalk between the macroautophagic degradation pathway and phagocytosis.

Role of MicroRNA-150 and Glycoprotein Nonmetastatic Melanoma Protein B in Angiogenesis during Hyperoxia-Induced Neonatal Lung Injury

“…Previous studies have shown that GPNMB enhances tissue repair by inducing autophagy and also promotes angiogenesis during tumor growth (36,37,40). We have recently identified GPNMB as one of the targets for miR-150 (34).…”

“…The mechanisms for the resistance in KO neonates are unknown. A recent study has implicated GPNMB in tissue protection by promoting autophagy (40), which induces the autophagy process by directly binding to a microtubule-associated protein 1A/1B-light chain 3/autophagyrelated protein 8, thereby enhancing the fusion of an autophagosome with a lysosome. The induction of autophagy further helps in clearing cellular debris, thus reducing inflammation and cellular injury.…”

Deficient Autophagy Results in Mitochondrial Dysfunction and FSGS

“…32 Grids were scanned using a Philips 410 electron microscope for mouse studies (Philips Export BV, Eindhoven, The Netherlands) and a JEOL 1011 electron microscope (Japan) for human studies.…”

Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis

“…A part of the reparative process involves phagocytosis and clearance of dead cells, debris, and oxidized matrix. Reparative macrophages express high levels of scavenger receptors and lysosomal pathway proteins, including the transmembrane glycoprotein gpNMB (60,62), which serve this clearance purpose. In addition, such reparative macrophages produce growth factors, which stimulate tubular cell and microvascular regeneration.…”