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A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment

Aggregation of human wild-type transthyretin (hTTR), a homo-tetrameric plasma protein, leads to acquired senile systemic amyloidosis (SSA), recently recognised as a major cause of cardiomyopathies in 1–3% older adults. Fragmented hTTR is the standard composition of amyloid deposits in SSA, but the p...

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Autores principales: Peterle, Daniele, Pontarollo, Giulia, Spada, Stefano, Brun, Paola, Palazzi, Luana, Sokolov, Alexej V., Spolaore, Barbara, Polverino de Laureto, Patrizia, Vasilyev, Vadim B., Castagliuolo, Ignazio, De Filippis, Vincenzo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733459/
https://www.ncbi.nlm.nih.gov/pubmed/33311636
http://dx.doi.org/10.1038/s42003-020-01493-0
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author Peterle, Daniele
Pontarollo, Giulia
Spada, Stefano
Brun, Paola
Palazzi, Luana
Sokolov, Alexej V.
Spolaore, Barbara
Polverino de Laureto, Patrizia
Vasilyev, Vadim B.
Castagliuolo, Ignazio
De Filippis, Vincenzo
author_facet Peterle, Daniele
Pontarollo, Giulia
Spada, Stefano
Brun, Paola
Palazzi, Luana
Sokolov, Alexej V.
Spolaore, Barbara
Polverino de Laureto, Patrizia
Vasilyev, Vadim B.
Castagliuolo, Ignazio
De Filippis, Vincenzo
author_sort Peterle, Daniele
collection PubMed
description Aggregation of human wild-type transthyretin (hTTR), a homo-tetrameric plasma protein, leads to acquired senile systemic amyloidosis (SSA), recently recognised as a major cause of cardiomyopathies in 1–3% older adults. Fragmented hTTR is the standard composition of amyloid deposits in SSA, but the protease(s) responsible for amyloidogenic fragments generation in vivo is(are) still elusive. Here, we show that subtilisin secreted from Bacillus subtilis, a gut microbiota commensal bacterium, translocates across a simulated intestinal epithelium and cleaves hTTR both in solution and human plasma, generating the amyloidogenic fragment hTTR(59–127), which is also found in SSA amyloids in vivo. To the best of our knowledge, these findings highlight a novel pathogenic mechanism for SSA whereby increased permeability of the gut mucosa, as often occurs in elderly people, allows subtilisin (and perhaps other yet unidentified bacterial proteases) to reach the bloodstream and trigger generation of hTTR fragments, acting as seeding nuclei for preferential amyloid fibrils deposition in the heart.
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spelling pubmed-77334592020-12-17 A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment Peterle, Daniele Pontarollo, Giulia Spada, Stefano Brun, Paola Palazzi, Luana Sokolov, Alexej V. Spolaore, Barbara Polverino de Laureto, Patrizia Vasilyev, Vadim B. Castagliuolo, Ignazio De Filippis, Vincenzo Commun Biol Article Aggregation of human wild-type transthyretin (hTTR), a homo-tetrameric plasma protein, leads to acquired senile systemic amyloidosis (SSA), recently recognised as a major cause of cardiomyopathies in 1–3% older adults. Fragmented hTTR is the standard composition of amyloid deposits in SSA, but the protease(s) responsible for amyloidogenic fragments generation in vivo is(are) still elusive. Here, we show that subtilisin secreted from Bacillus subtilis, a gut microbiota commensal bacterium, translocates across a simulated intestinal epithelium and cleaves hTTR both in solution and human plasma, generating the amyloidogenic fragment hTTR(59–127), which is also found in SSA amyloids in vivo. To the best of our knowledge, these findings highlight a novel pathogenic mechanism for SSA whereby increased permeability of the gut mucosa, as often occurs in elderly people, allows subtilisin (and perhaps other yet unidentified bacterial proteases) to reach the bloodstream and trigger generation of hTTR fragments, acting as seeding nuclei for preferential amyloid fibrils deposition in the heart. Nature Publishing Group UK 2020-12-11 /pmc/articles/PMC7733459/ /pubmed/33311636 http://dx.doi.org/10.1038/s42003-020-01493-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Peterle, Daniele
Pontarollo, Giulia
Spada, Stefano
Brun, Paola
Palazzi, Luana
Sokolov, Alexej V.
Spolaore, Barbara
Polverino de Laureto, Patrizia
Vasilyev, Vadim B.
Castagliuolo, Ignazio
De Filippis, Vincenzo
A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment
title A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment
title_full A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment
title_fullStr A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment
title_full_unstemmed A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment
title_short A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment
title_sort serine protease secreted from bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733459/
https://www.ncbi.nlm.nih.gov/pubmed/33311636
http://dx.doi.org/10.1038/s42003-020-01493-0
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