ACTIN-DIRECTED TOXIN. ACD toxin-produced actin oligomers poison formin-controlled actin polymerization

David B Heisler; Elena Kudryashova; Dmitry O Grinevich; Cristian Suarez; Jonathan D Winkelman; Konstantin G Birukov; Sainath R Kotha; Narasimham L Parinandi; Dimitrios Vavylonis; David R Kovar; Dmitri S Kudryashov

doi:10.1126/science.aab4090

ACTIN-DIRECTED TOXIN. ACD toxin-produced actin oligomers poison formin-controlled actin polymerization

Science. 2015 Jul 31;349(6247):535-9. doi: 10.1126/science.aab4090.

Affiliations

¹ Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA. The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA.
² Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA. kudryashov.1@osu.edu kudryashova.1@osu.edu.
³ Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
⁴ Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA.
⁵ Section of Pulmonary and Critical Care and Lung Injury Center, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
⁶ Lipid Signaling and Lipidomics Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
⁷ Department of Physics, Lehigh University, Bethlehem, PA 18015, USA.
⁸ Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA. Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
⁹ Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA. The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA. kudryashov.1@osu.edu kudryashova.1@osu.edu.

Abstract

The actin cross-linking domain (ACD) is an actin-specific toxin produced by several pathogens, including life-threatening spp. of Vibrio cholerae, Vibrio vulnificus, and Aeromonas hydrophila. Actin cross-linking by ACD is thought to lead to slow cytoskeleton failure owing to a gradual sequestration of actin in the form of nonfunctional oligomers. Here, we found that ACD converted cytoplasmic actin into highly toxic oligomers that potently "poisoned" the ability of major actin assembly proteins, formins, to sustain actin polymerization. Thus, ACD can target the most abundant cellular protein by using actin oligomers as secondary toxins to efficiently subvert cellular functions of actin while functioning at very low doses.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Actins / metabolism*
Animals
Antigens, Bacterial / chemistry*
Antigens, Bacterial / genetics
Antigens, Bacterial / toxicity*
Bacterial Toxins / chemistry*
Bacterial Toxins / genetics
Bacterial Toxins / toxicity*
Cell Line
Fetal Proteins / antagonists & inhibitors*
Formins
Intestinal Mucosa / drug effects
Intestinal Mucosa / metabolism
Microfilament Proteins / antagonists & inhibitors*
Nuclear Proteins / antagonists & inhibitors*
Polymerization / drug effects
Protein Structure, Tertiary
Rats

Substances

Actins
Antigens, Bacterial
Bacterial Toxins
Fetal Proteins
Formins
Microfilament Proteins
Nuclear Proteins
anthrax toxin

ACTIN-DIRECTED TOXIN. ACD toxin-produced actin oligomers poison formin-controlled actin polymerization

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

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