Pathogen induced upregulation of the lysosomal maturation protein, Melanoregulin (MREG) in macrophages

Abstract

In professional phagocytic cells such as the retinal Pigment epithelial (RPE) cells, the product of the Mregdsu gene, melanoregulin (Mreg) plays a critical role in lysosome‐dependent phagosome maturation and degradation of phagocytosed photoreceptor debris. MREG null mice demonstrate defects in lysosomal maturation, alkalanization of lysosomal pH, incorrect processing of key degradative enzymes such as cathepsin‐D resulting in the accumulation of the engulfed cargo. We hypothesize that in macrophages Mreg plays a similar in the phagolysosmal dependent clearance of engulfed microbial pathogens. Treatment of macrophage cells, J774 with purified lipopolysaccharide (LPS) from E. coli and the periodontal pathogen, P. gingivalis resulted in the transcriptional up regulation of Mreg mRNA and protein. Treatment of J774 cells with the PI‐3‐kinase inhibitors, LY29004 and Wortmanin inhibited LPS induced expression of Mreg. Analysis of Mreg promoter indicated conservation in sequence and transcription factor binding sites such as SP1 and AP1. Mreg induction in macrophages challenged with bacterial endotoxins and its proposed role in lysosomal maturation suggests that Mreg may have a pivotal role to play in the clearance of microbial pathogens.