Pathogenic Leptospira Evolved a Unique Gene Family Comprised of Ricin B-Like Lectin Domain-Containing Cytotoxins
Leptospirosis is a globally important neglected zoonotic disease. Previous data suggest that a family of virulence-modifying (VM) proteins (PF07598) is a distinctive feature of group I pathogenic that evolved as important virulence determinants. Here, we show that one such VM protein, LA3490 (also k...
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Published in | Frontiers in microbiology Vol. 13; p. 859680 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
Frontiers Media S.A
29.03.2022
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Subjects | |
Online Access | Get full text |
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Summary: | Leptospirosis is a globally important neglected zoonotic disease. Previous data suggest that a family of virulence-modifying (VM) proteins (PF07598) is a distinctive feature of group I pathogenic
that evolved as important virulence determinants. Here, we show that one such VM protein, LA3490 (also known as Q8F0K3), is expressed by
serovar Lai, as a secreted genotoxin that is potently cytotoxic to human cells. Structural homology searches using Phyre2 suggested that VM proteins are novel R-type lectins containing tandem N-terminal ricin B-chain-like β-trefoil domains. Recombinant LA3490 (rLA3490) and an N-terminal fragment, t3490, containing only the predicted ricin B domain, bound to the terminal galactose and N-acetyl-galactosamine residues, asialofetuin, and directly competed for asialofetuin-binding sites with recombinant ricin B chain. t3490 alone was sufficient for binding, both to immobilized asialofetuin and to the HeLa cell surface but was neither internalized nor cytotoxic. Treatment of HeLa cells with rLA3490 led to cytoskeleton disassembly, caspase-3 activation, and nuclear fragmentation, and was rapidly cytolethal. rLA3490 had DNase activity on mammalian and bacterial plasmid DNA. The combination of cell surface binding, internalization, nuclear translocation, and DNase functions indicate that LA3490 and other VM proteins evolved as novel forms of the bacterial AB domain-containing toxin paradigm. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This article was submitted to Systems Microbiology, a section of the journal Frontiers in Microbiology Edited by: David Kornspan, Kimron Veterinary Institute, Israel Reviewed by: Rich Olson, Wesleyan University, United States; Dror Tobi, Ariel University, Israel; Angela Silva Barbosa, Butantan Institute, Brazil |
ISSN: | 1664-302X 1664-302X |
DOI: | 10.3389/fmicb.2022.859680 |