Plasminogen activation triggers transthyretin amyloidogenesis in vitro

P. Patrizia Mangione, Guglielmo Verona, Alessandra Corazza, Julien Marcoux, Diana Canetti, Sofia Giorgetti, Sara Raimondi, Monica Stoppini, Marilena Esposito, Annalisa Relini, Claudio Canale, Maurizia Valli, Loredana Marchese, Giulia Faravelli, Laura Obici, Philip N. Hawkins, Graham W. Taylor, Julian D. Gillmore, Mark B. Pepys, Vittorio Bellotti

Research output: Contribution to journalArticle

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Abstract

Systemic amyloidosis is a usually fatal disease caused by extracellular accumulation of abnormal protein fibers, amyloid fibrils, derived by misfolding and aggregation of soluble globular plasma protein precursors. Both WT and genetic variants of the normal plasma protein transthyretin (TTR) form amyloid, but neither the misfolding leading to fibrillogenesis nor the anatomical localization of TTR amyloid deposition are understood. Wehave previously shown that, under physiological conditions, trypsin cleaves human TTR in a mechano-enzymatic mechanism that generates abundant amyloid fibrils in vitro. In sharp contrast, the widely used in vitro model of denaturation and aggregation of TTR by prolonged exposure to pH 4.0 yields almost no clearly defined amyloid fibrils. However, the exclusive duodenal location of trypsin means that this enzyme cannot contribute to systemic extracellular TTR amyloid deposition in vivo. Here, we therefore conducted a bioinformatics search for systemically active tryptic proteases with appropriate tissue distribution, which unexpectedly identified plasmin as the leading candidate. We confirmed that plasmin, just as trypsin, selectively cleaves human TTR between residues 48 and 49 under physiological conditions in vitro. Truncated and full-length protomers are then released from the native homotetramer and rapidly aggregate into abundant fibrils indistinguishable from ex vivo TTR amyloid. Our findings suggest that physiological fibrinolysis is likely to play a critical role in TTR amyloid formation in vivo. Identification of this surprising intersection between two hitherto unrelated pathways opens new avenues for elucidating the mechanisms of TTR amyloidosis, for seeking susceptibility risk factors, and for therapeutic innovation.

Original languageEnglish
Pages (from-to)14192-14199
Number of pages8
JournalJournal of Biological Chemistry
Volume293
Issue number37
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Prealbumin
Plasminogen
Amyloid
Chemical activation
Trypsin
Fibrinolysin
Blood Proteins
Agglomeration
Protein Precursors
In Vitro Techniques
Protein Subunits
Denaturation
Fibrinolysis
Amyloidosis
Tissue Distribution
Computational Biology
Bioinformatics
Peptide Hydrolases
Innovation
Tissue

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Mangione, P. P., Verona, G., Corazza, A., Marcoux, J., Canetti, D., Giorgetti, S., ... Bellotti, V. (2018). Plasminogen activation triggers transthyretin amyloidogenesis in vitro. Journal of Biological Chemistry, 293(37), 14192-14199. https://doi.org/10.1074/jbc.RA118.003990

Plasminogen activation triggers transthyretin amyloidogenesis in vitro. / Mangione, P. Patrizia; Verona, Guglielmo; Corazza, Alessandra; Marcoux, Julien; Canetti, Diana; Giorgetti, Sofia; Raimondi, Sara; Stoppini, Monica; Esposito, Marilena; Relini, Annalisa; Canale, Claudio; Valli, Maurizia; Marchese, Loredana; Faravelli, Giulia; Obici, Laura; Hawkins, Philip N.; Taylor, Graham W.; Gillmore, Julian D.; Pepys, Mark B.; Bellotti, Vittorio.

In: Journal of Biological Chemistry, Vol. 293, No. 37, 01.01.2018, p. 14192-14199.

Research output: Contribution to journalArticle

Mangione, PP, Verona, G, Corazza, A, Marcoux, J, Canetti, D, Giorgetti, S, Raimondi, S, Stoppini, M, Esposito, M, Relini, A, Canale, C, Valli, M, Marchese, L, Faravelli, G, Obici, L, Hawkins, PN, Taylor, GW, Gillmore, JD, Pepys, MB & Bellotti, V 2018, 'Plasminogen activation triggers transthyretin amyloidogenesis in vitro', Journal of Biological Chemistry, vol. 293, no. 37, pp. 14192-14199. https://doi.org/10.1074/jbc.RA118.003990
Mangione PP, Verona G, Corazza A, Marcoux J, Canetti D, Giorgetti S et al. Plasminogen activation triggers transthyretin amyloidogenesis in vitro. Journal of Biological Chemistry. 2018 Jan 1;293(37):14192-14199. https://doi.org/10.1074/jbc.RA118.003990
Mangione, P. Patrizia ; Verona, Guglielmo ; Corazza, Alessandra ; Marcoux, Julien ; Canetti, Diana ; Giorgetti, Sofia ; Raimondi, Sara ; Stoppini, Monica ; Esposito, Marilena ; Relini, Annalisa ; Canale, Claudio ; Valli, Maurizia ; Marchese, Loredana ; Faravelli, Giulia ; Obici, Laura ; Hawkins, Philip N. ; Taylor, Graham W. ; Gillmore, Julian D. ; Pepys, Mark B. ; Bellotti, Vittorio. / Plasminogen activation triggers transthyretin amyloidogenesis in vitro. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 37. pp. 14192-14199.
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AU - Relini, Annalisa

AU - Canale, Claudio

AU - Valli, Maurizia

AU - Marchese, Loredana

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AU - Obici, Laura

AU - Hawkins, Philip N.

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