Loss of melanoregulin (MREG) enhances cathepsin-D secretion by the retinal pigment epithelium
Open accessAbstract
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.
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RPE from Mreg−/− mice have increased secretion of pro-cathepsin D into the extracellular medium.
“RPE from Mreg−/− mice have decreased levels of the mature enzyme (Damek-Poprawa et al., 2009), and increased secretion of pro-cathepsin D into the extracellular medium (Frost et al., 2013).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Frost et al., 2013
Melanoregulin (MREG) is a small, highly charged protein that localizes to lysosomes.
“Similarly, melanoregulin (MREG), a small, highly-charged protein that localizes to lysosomes (Frost et al., 2013), is important for cathepsin D maturation.”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Frost et al., 2013
MREG is important for cathepsin D maturation.
“Similarly, melanoregulin (MREG), a small, highly-charged protein that localizes to lysosomes (Frost et al., 2013), is important for cathepsin D maturation.”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Frost et al., 2013
Loss of MREG, an LC3B binding partner, contributes to a delay in phagosome maturation and lysosomal exocytosis, as well as basal laminar thickening in older mice.
“Loss of MREG, an LC3B binding partner contributes to a delay in phagosome maturation (Damek-Poprawa et al., 2009) and lysosomal exocytosis, as well as basal laminar thickening in older mice (Frost et al., 2013).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Frost et al., 2013
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The cell biology of the retinal pigment epithelium
Lakkaraju, A., Umapathy, A., Tan, L. X., Daniele, L., Philp, N. J., Boesze-Battaglia, K., & Williams, D. S. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100846 · Cited by 422 · see citing works
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Self-citationFrost, L. S., Lopes, V. S., Bragin, A., Reyes-Reveles, J., Brancato, J., Cohen, A., Mitchell, C. H., Williams, D. S., & Boesze-Battaglia, K. (2015) · Molecular Neurobiology · doi:10.1007/s12035-014-8920-5 · Cited by 63 · see citing works
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- Authors
- FROST, L. S., LOPES, V. S., STEFANO, F. P., BRAGIN, A., WILLIAMS, D. S., MITCHELL, C. H., & BOESZE-BATTAGLIA, K.
- Affiliations
- University of Pennsylvania (US)
- University of California, Los Angeles (US)
- Venue
- Visual Neuroscience
- Publisher
- Maximum Academic Press
- Published
- 2013-04-23
- Volume
- 30
- Issue
- 3
- Pages
- 55-64
- ISSN
- 0952-5238 (ISSN-L)
- 1469-8714
- PMC
- PMC3912860
- OpenAlex
- W2150129806
- Cited by
- 9
- References
- 61
- Citations by year
- 2023: 1 · 2022: 1 · 2021: 1 · 2020: 3 · 2017: 2 · 2014: 1
- FWCI
- 0.15
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Visual Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ScholarlyCommons (University of Pennsylvania) (submittedVersion)
- Scholarly Commons (University of Pennsylvania) (submittedVersion)
- Funders
- National Institutes of Health
- National Eye Institute (EY001583, R01EY013434, R01EY010420, R01 EY07042, R21EY018705, R01EY007042, P30EY001583)
- National Center for Research Resources (S10RR026365)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- cathepsin D, retinal pigment epithelium, phagocytosis, laminin, retinal homeostasis, retinal disease
- MeSH terms
- Analysis of Variance, Animals, Carrier Proteins, Cathepsin D, Cell Membrane, Cells, Cultured, Gene Expression Regulation, L-Lactate Dehydrogenase, Mice, Inbred C57BL, Mice, Transgenic, Retina, Transduction, Genetic, Microscopy, Immunoelectron, Microscopy, Confocal, Adaptor Proteins, Vesicular Transport, RNA, Small Interfering, Intracellular Signaling Peptides and Proteins, Mice, Retinal Pigment Epithelium
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