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Loss of melanoregulin (MREG) enhances cathepsin-D secretion by the retinal pigment epithelium

Published online by Cambridge University Press:  23 April 2013

LAURA S. FROST ,
VANDA S. LOPES ,
FRANK P. STEFANO ,
ALVINA BRAGIN ,
DAVID S. WILLIAMS ,
CLAIRE H. MITCHELL  and
KATHLEEN BOESZE-BATTAGLIA
LAURA S. FROST
Affiliation:
Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
VANDA S. LOPES
Affiliation:
Departments of Ophthalmology and Neurobiology, Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, California
FRANK P. STEFANO
Affiliation:
Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
ALVINA BRAGIN
Affiliation:
Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
DAVID S. WILLIAMS
Affiliation:
Departments of Ophthalmology and Neurobiology, Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, California
CLAIRE H. MITCHELL
Affiliation:
Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
KATHLEEN BOESZE-BATTAGLIA*
Affiliation:
Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
*
Address correspondence to: Kathleen Boesze-Battaglia, Department of Biochemistry, University of Pennsylvania, Philadelphia, PA 19104. E-mail: [email protected]
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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 Mregdsu/dsu mouse, we observe increased basal laminin. Loss of the Mregdsu 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.

Keywords

Retinal pigment epitheliumCathepsin-D processingPhagocytosisProtease secretion
Type
Research Articles
Information
Visual Neuroscience , Volume 30 , Issue 3 , May 2013 , pp. 55 - 64
Copyright
Copyright © Cambridge University Press 2013 

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