HTRA1, an age-related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1

Michael K Lin; Jin Yang; Chun Wei Hsu; Anuradha Gore; Alexander G Bassuk; Lewis M Brown; Ryan Colligan; Jesse D Sengillo; Vinit B Mahajan; Stephen H Tsang

doi:10.1111/acel.12710

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HTRA1, an age-related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1

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HTRA1, an age-related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1

Michael K Lin, Jin Yang, Chun Wei Hsu, Anuradha Gore, Alexander G Bassuk, Lewis M Brown, Ryan Colligan, Jesse D Sengillo, Vinit B Mahajan and Stephen H Tsang

Aging cell, Vol.17(4), pp.e12710-n/a

08/2018

DOI: 10.1111/acel.12710

PMCID: PMC6052470

PMID: 29730901

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Abstract

High-temperature requirement protein A1 (HTRA1) is a serine protease secreted by a number of tissues including retinal pigment epithelium (RPE). A promoter variant of the gene encoding HTRA1 is part of a mutant allele that causes increased HTRA1 expression and contributed to age-related macular degeneration (AMD) in genomewide association studies. AMD is characterized by pathological development of drusen, extracellular deposits of proteins and lipids on the basal side of RPE. The molecular pathogenesis of AMD is not well understood, and understanding dysregulation of the extracellular matrix may be key. We assess the high-risk genotype at 10q26 by proteomic comparison of protein levels of RPE cells with and without the mutation. We show HTRA1 protein level is increased in high-risk RPE cells along with several extracellular matrix proteins, including known HTRA1 cleavage targets LTBP-1 and clusterin. In addition, two novel targets of HTRA1 have been identified: EFEMP1, an extracellular matrix protein mutated in Doyne honeycomb retinal dystrophy, a genetic eye disease similar to AMD, and thrombospondin 1 (TSP1), an inhibitor of angiogenesis. Our data support the role of RPE extracellular deposition with potential effects in compromised barrier to neovascularization in exudative AMD.

High-Temperature Requirement A Serine Peptidase 1 - metabolism

Macular Degeneration - metabolism

Retinal Pigment Epithelium - metabolism

Macular Degeneration - genetics

Humans

Cells, Cultured

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism

Extracellular Matrix Proteins - metabolism

High-Temperature Requirement A Serine Peptidase 1 - genetics

Details

Title: Subtitle: HTRA1, an age-related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1
Creators: Michael K Lin - Jonas Children's Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Departments of Ophthalmology, Pathology & Cell Biology, Institute of Human Nutrition, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
Jin Yang - Tianjin Medical University Eye Hospital, Tianjin, China
Chun Wei Hsu - Jonas Children's Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Departments of Ophthalmology, Pathology & Cell Biology, Institute of Human Nutrition, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
Anuradha Gore - Omics Laboratory, Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA, USA
Alexander G Bassuk - Department of Pediatrics and Neurology, University of Iowa, Iowa City, IA, USA
Lewis M Brown - Quantitative Proteomics and Metabolomics Center, Department of Biological Sciences, Columbia University, New York, NY, USA
Ryan Colligan - Quantitative Proteomics and Metabolomics Center, Department of Biological Sciences, Columbia University, New York, NY, USA
Jesse D Sengillo - Jonas Children's Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Departments of Ophthalmology, Pathology & Cell Biology, Institute of Human Nutrition, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
Vinit B Mahajan - Palo Alto Veterans Administration, Palo Alto, CA, USA
Stephen H Tsang - Jonas Children's Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Departments of Ophthalmology, Pathology & Cell Biology, Institute of Human Nutrition, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
Resource Type: Journal article
Publication Details: Aging cell, Vol.17(4), pp.e12710-n/a
DOI: 10.1111/acel.12710
PMID: 29730901
PMCID: PMC6052470
NLM abbreviation: Aging Cell
ISSN: 1474-9718
eISSN: 1474-9726
Publisher: England
Grant note: R01 EY025225 / NEI NIH HHS R01 EY018213 / NEI NIH HHS R01 EY026682 / NEI NIH HHS R01 EY024665 / NEI NIH HHS R01 EY024698 / NEI NIH HHS R21 AG050437 / NIA NIH HHS
Language: English
Date published: 08/2018
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
Record Identifier: 9984070496402771

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