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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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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. |
format | Online Article Text |
id | pubmed-7733459 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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