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

• Published in: Communications biology Vol. 3; no. 1; p. 764
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 11.12.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Amyloidogenesis; Amyloidosis; Bacillus subtilis; Biology; Digestive system; Digestive tract; Epithelium; Fibrils; Intestinal microflora; Intestine; Microbiota; Mucosa; Older people; Permeability; Protein seeding; Serine; Serine proteinase; Subtilisin; Transthyretin
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-020-01493-0

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.