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

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.

• Authors: 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
• Journal: Aging cell (Aging Cell) Vol. 17 Issue 4 Pg. e12710 (08 2018) ISSN: 1474-9726 [Electronic] England
• PMID: 29730901 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• EFEMP1 protein, human
• Extracellular Matrix Proteins
• SPZ1 protein, human
• High-Temperature Requirement A Serine Peptidase 1
• HtrA1 protein, human

Topics

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (metabolism)
• Cells, Cultured
• Extracellular Matrix Proteins (metabolism)
• High-Temperature Requirement A Serine Peptidase 1 (genetics, metabolism)
• Humans
• Macular Degeneration (genetics, metabolism)
• Retinal Pigment Epithelium (metabolism)