Late-onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1

Anil Chekuri, Katarzyna Zientara-Rytter, Angel Soto-Hermida, Shyamanga Borooah, Marina Voronchikhina, Pooja Biswas, Virender Kumar, David Goodsell, Caroline Hayward, Peter Shaw, Chloe Stanton, Donita Garland, Suresh Subramani, Radha Ayyagari

Research output: Contribution to journalArticle

Abstract

Late-onset retinal degeneration (L-ORD) is an autosomal dominant macular degeneration characterized by the formation of sub-retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L-ORD results from mutations in the C1q-tumor necrosis factor-5 protein (CTRP5), encoded by the CTRP5/C1QTNF5 gene. To understand the mechanism underlying L-ORD pathology, we used a human cDNA library yeast two-hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane/choroid (BM-Ch) from wild-type (Wt), heterozygous S163R Ctrp5 mutation knock-in (Ctrp5S163R/wt), and homozygous knock-in (Ctrp5S163R/S163R) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C-terminal PDZ-binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R-CTRP5 protein also binds to HTRA1 but is resistant to HTRA1-mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM-Ch of Ctrp5S163R/S163R and Ctrp5S163R/wt mice compared with Wt. Additional extracellular matrix (ECM) components that are HTRA1 substrates also accumulated in these mice. These results implicate HTRA1 and its interaction with CTRP5 in L-ORD pathology.

Original languageEnglish (US)
Article numbere13011
JournalAging cell
Volume18
Issue number6
DOIs
StatePublished - Dec 1 2019

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All Science Journal Classification (ASJC) codes

  • Aging
  • Cell Biology

Keywords

  • CTRP5
  • ECM remodeling
  • HTRA1
  • L-ORD
  • age-related macular degeneration
  • drusen
  • sub-RPE deposits

Cite this

Chekuri, A., Zientara-Rytter, K., Soto-Hermida, A., Borooah, S., Voronchikhina, M., Biswas, P., Kumar, V., Goodsell, D., Hayward, C., Shaw, P., Stanton, C., Garland, D., Subramani, S., & Ayyagari, R. (2019). Late-onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1. Aging cell, 18(6), [e13011]. https://doi.org/10.1111/acel.13011