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Casper Rasmussen

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

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The serine protease HtrA1 cleaves misfolded transforming growth factor β-induced protein (TGFBIp) and induces amyloid formation. / Poulsen, Ebbe Toftgaard; Nielsen, Nadia Sukusu; Scavenius, Carsten; Mogensen, Emilie Hage; Risør, Michael W.; Runager, Kasper; Lukassen, Marie V.; Rasmussen, Casper B.; Christiansen, Gunna; Richner, Mette; Vorum, Henrik; Enghild, Jan J.

I: Journal of Biological Chemistry, Bind 294, Nr. 31, 08.2019, s. 11817-11828.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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Poulsen, Ebbe Toftgaard ; Nielsen, Nadia Sukusu ; Scavenius, Carsten ; Mogensen, Emilie Hage ; Risør, Michael W. ; Runager, Kasper ; Lukassen, Marie V. ; Rasmussen, Casper B. ; Christiansen, Gunna ; Richner, Mette ; Vorum, Henrik ; Enghild, Jan J. / The serine protease HtrA1 cleaves misfolded transforming growth factor β-induced protein (TGFBIp) and induces amyloid formation. I: Journal of Biological Chemistry. 2019 ; Bind 294, Nr. 31. s. 11817-11828.

Bibtex

@article{27ef2f4edc2b4d5c80414b65088443b9,
title = "The serine protease HtrA1 cleaves misfolded transforming growth factor β-induced protein (TGFBIp) and induces amyloid formation",
abstract = "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. ",
keywords = "BETA-IG-H3, BIGH3, CORNEA, HTRA1, IDENTIFICATION, LATTICE, MATRIX, MECHANISMS, MUTATIONS, PROTEOMICS, REVEALS, SUSCEPTIBILITY, 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 beta-induced protein (TGFBIp), Extracellular Matrix Proteins/chemistry, Humans, Chromatography, High Pressure Liquid, Amyloid/metabolism, Tandem Mass Spectrometry, High-Temperature Requirement A Serine Peptidase 1/genetics, Peptides/analysis, Aged, 80 and over, Protein Domains, Mutagenesis, Site-Directed, Recombinant Proteins/biosynthesis, Protein Folding, Corneal Diseases/metabolism, Transforming Growth Factor beta/chemistry, Cornea/metabolism",
author = "Poulsen, {Ebbe Toftgaard} and Nielsen, {Nadia Sukusu} and Carsten Scavenius and Mogensen, {Emilie Hage} and Ris{\o}r, {Michael W.} and Kasper Runager and Lukassen, {Marie V.} and Rasmussen, {Casper B.} and Gunna Christiansen and Mette Richner and Henrik Vorum and Enghild, {Jan J.}",
note = "{\textcopyright} 2019 Poulsen et al.",
year = "2019",
month = aug,
doi = "10.1074/jbc.RA119.009050",
language = "English",
volume = "294",
pages = "11817--11828",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "31",

}

RIS

TY - JOUR

T1 - The serine protease HtrA1 cleaves misfolded transforming growth factor β-induced protein (TGFBIp) and induces amyloid formation

AU - Poulsen, Ebbe Toftgaard

AU - Nielsen, Nadia Sukusu

AU - Scavenius, Carsten

AU - Mogensen, Emilie Hage

AU - Risør, Michael W.

AU - Runager, Kasper

AU - Lukassen, Marie V.

AU - Rasmussen, Casper B.

AU - Christiansen, Gunna

AU - Richner, Mette

AU - Vorum, Henrik

AU - Enghild, Jan J.

N1 - © 2019 Poulsen et al.

PY - 2019/8

Y1 - 2019/8

N2 - 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.

AB - 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.

KW - BETA-IG-H3

KW - BIGH3

KW - CORNEA

KW - HTRA1

KW - IDENTIFICATION

KW - LATTICE

KW - MATRIX

KW - MECHANISMS

KW - MUTATIONS

KW - PROTEOMICS

KW - REVEALS

KW - SUSCEPTIBILITY

KW - amyloid

KW - cornea

KW - corneal dystrophy

KW - eye disorder

KW - granular corneal dystrophy (GCD)

KW - high-temperature requirement protein A1 (HtrA1)

KW - lattice corneal dystrophy (LCD)

KW - protease

KW - protein folding

KW - protein misfolding

KW - protein turnover

KW - proteolytic processing

KW - transforming growth factor beta-induced protein (TGFBIp)

KW - Extracellular Matrix Proteins/chemistry

KW - Humans

KW - Chromatography, High Pressure Liquid

KW - Amyloid/metabolism

KW - Tandem Mass Spectrometry

KW - High-Temperature Requirement A Serine Peptidase 1/genetics

KW - Peptides/analysis

KW - Aged, 80 and over

KW - Protein Domains

KW - Mutagenesis, Site-Directed

KW - Recombinant Proteins/biosynthesis

KW - Protein Folding

KW - Corneal Diseases/metabolism

KW - Transforming Growth Factor beta/chemistry

KW - Cornea/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85070745851&partnerID=8YFLogxK

U2 - 10.1074/jbc.RA119.009050

DO - 10.1074/jbc.RA119.009050

M3 - Journal article

C2 - 31197037

AN - SCOPUS:85070745851

VL - 294

SP - 11817

EP - 11828

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 31

ER -