title: Loss of melanoregulin (MREG) enhances cathepsin-D secretion by the retinal pigment epithelium.
abstract: Cathepsin-D (Cat-D) is a major proteolytic enzyme in phagocytic cells. In the retinal pigment epithelium (RPE), it is responsible for the daily degradation of photoreceptor outer segments (POSs) to maintain retinal homeostasis. Melanoregulin (MREG)-mediated loss of phagocytic capacity has been linked to diminished intracellular Cat-D activity. Here, we demonstrate that loss of MREG enhances the secretion of intermediate Cat-D (48 kDa), resulting in a net enhancement of extracellular Cat-D activity. These results suggest that MREG is required to maintain Cat-D homeostasis in the RPE and likely plays a protective role in retinal health. In this regard, in the Mreg dsu/dsu mouse, we observe increased basal laminin. Loss of the Mreg dsu allele is not lethal and therefore leads to slow age-dependent changes in the RPE. Thus, we propose that this model will allow us to study potential dysregulatory functions of Cat-D in retinal disease.
authors.affiliation: Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Frost
authors.forename: Vanda S
authors.initials: VS
authors.lastname: Lopes
authors.forename: Frank P
authors.initials: FP
authors.lastname: Stefano
authors.forename: Alvina
authors.initials: A
authors.lastname: Bragin
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: Claire H
authors.initials: CH
authors.lastname: Mitchell
authors.forename: Kathleen
authors.initials: K
authors.lastname: Boesze-Battaglia
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000704:Analysis of Variance; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002402:Cathepsin D / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology*; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000648:ultrastructure; D014161:Transduction, Genetic
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C518334:melanoregulin protein, mouse; D007770:L-Lactate Dehydrogenase; D002402:Cathepsin D