Proteomics

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TcdB of Clostridioides difficile mediates necrosis in epithelial cells and is depend on RAS


ABSTRACT: A Clostridioides difficile infection (CDI) is the most common nosocomial infection worldwide. The main virulence factors are TcdA and TcdB, which inhibit small Rho-GTPases. Inhibition of small Rho-GTPases leads to the so-called cytopathic effect, a reorganization of the actin cytoskeleton, an impairment of the colon epithelium barrier function, and inflammation. Additionally, TcdB induces a necrotic cell death termed pyknosis in vitro independently from its glucosyltransferas-es characterized by chromatin condensation and ROS production. To understand the underlying mechanism of this pyknotic effect, we conducted a large-scale phosphoproteomic study. We in-cluded the analysis of alterations in the phosphoproteome after treatment with TcdA, that was investigated for the first time. TcdA exhibit no glucosyltransferase-independent effect and was, thus, a good control to elucidate the underlying mechanism of the glucosyltransferase inde-pendent effect of TcdB. We found RAS to be a central upstream regulator for the glucosyltrans-ferase independent effect of TcdB. Inhibition of RAS leads to a 68% reduction in necrosis. Further analysis revealed apolipoprotein C-III (APOC3) as a possible crucial factor of CDI induced in-flammation in vivo.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Florian Stieglitz  

LAB HEAD: Andreas Pich

PROVIDER: PXD031726 | Pride | 2022-05-19

REPOSITORIES: Pride

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Publications

TcdB of <i>Clostridioides difficile</i> Mediates RAS-Dependent Necrosis in Epithelial Cells.

Stieglitz Florian F   Gerhard Ralf R   Hönig Rabea R   Giehl Klaudia K   Pich Andreas A  

International journal of molecular sciences 20220412 8


A <i>Clostridioides difficile</i> infection (CDI) is the most common nosocomial infection worldwide. The main virulence factors of pathogenic <i>C. difficile</i> are TcdA and TcdB, which inhibit small Rho-GTPases. The inhibition of small Rho-GTPases leads to the so-called cytopathic effect, a reorganization of the actin cytoskeleton, an impairment of the colon epithelium barrier function and inflammation. Additionally, TcdB induces a necrotic cell death termed pyknosis in vitro independently fro  ...[more]

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