TY - JOUR

T1 - A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment

AU - Peterle, Daniele

AU - Pontarollo, Giulia

AU - Spada, Stefano

AU - Brun, Paola

AU - Palazzi, Luana

AU - Sokolov, Alexej V.

AU - Spolaore, Barbara

AU - Polverino de Laureto, Patrizia

AU - Vasilyev, Vadim B.

AU - Castagliuolo, Ignazio

AU - De Filippis, Vincenzo

N1 - Funding Information: Part of this work was presented at Proteine-2018 conference, May 28–30, 2018, Verona, Italy. Communication. P28. This work was supported by a Grant from the CaRiPaRo Foundation Excellence Research Project 2018—BPiTA n. 52012 to V.D.F. The postdoctoral fellowship of D.P. was funded by the and BPiTA project and by a PRID-2018 Grant from the University of Padua to B.S. The technical assistance of Dr. Federico Caicci in TEM analyses is gratefully acknowledged. V.D.F. gratefully thanks Prof. Maria Grazia Ferlin for introducing him to the transthyretin field and Dr. Daniele Dalzoppo for critically reading the manuscript. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85097491926&partnerID=8YFLogxK

U2 - 10.1038/s42003-020-01493-0

DO - 10.1038/s42003-020-01493-0

M3 - Article

C2 - 33311636

AN - SCOPUS:85097491926

VL - 3

JO - Communications Biology

JF - Communications Biology

SN - 2399-3642

SN - 2399-3642

IS - 1

M1 - 764

ER -