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J Biol Chem. 2019 Aug 2;294(31):11817-11828. doi: 10.1074/jbc.RA119.009050. Epub 2019 Jun 13.

The serine protease HtrA1 cleaves misfolded transforming growth factor β-induced protein (TGFBIp) and induces amyloid formation.

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Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark.
Interdisciplinary Nanoscience Center, Aarhus University, 8000 Aarhus, Denmark.
Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
Department of Ophthalmology, Aalborg University Hospital, 9000 Aalborg, Denmark.
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark


The serine protease high-temperature requirement protein A1 (HtrA1) is associated with protein-misfolding disorders such as Alzheimer's disease and transforming growth factor β-induced protein (TGFBIp)-linked corneal dystrophy. In this study, using several biochemical and biophysical approaches, including recombinant protein expression, LC-MS/MS and 2DE analyses, and thioflavin T (ThT) fluorescence assays for amyloid fibril detection, and FTIR assays, we investigated the role of HtrA1 both in normal TGFBIp turnover and in corneal amyloid formation. We show that HtrA1 can cleave WT TGFBIp but prefers amyloidogenic variants. Corneal TGFBIp is extensively processed in healthy people, resulting in C-terminal degradation products spanning the FAS1-4 domain of TGFBIp. We show here that HtrA1 cleaves the WT FAS1-4 domain only inefficiently, whereas the amyloidogenic FAS1-4 mutations transform this domain into a considerably better HTRA1 substrate. Moreover, HtrA1 cleavage of the mutant FAS1-4 domains generated peptides capable of forming in vitro amyloid aggregates. Significantly, these peptides have been previously identified in amyloid deposits in vivo, supporting the idea that HtrA1 is a causative agent for TGFBIp-associated amyloidosis in corneal dystrophy. In summary, our results indicate that TGFBIp is an HtrA1 substrate and that some mutations in the gene encoding TGFBIp cause aberrant HtrA1-mediated processing that results in amyloidogenesis in corneal dystrophies.


BIGH3; HTRA1; amyloid; cornea; corneal dystrophy; eye disorder; granular corneal dystrophy (GCD); high-temperature requirement protein A1 (HtrA1); lattice corneal dystrophy (LCD); protease; protein folding; protein misfolding; protein turnover; proteolytic processing; transforming growth factor β–induced protein (TGFBIp)

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