In the latest issue of Science, researchers from the University of Freiburg report on their discovery of a new mode of action of insecticidal toxins from Photorhabdus luminescens, a bacterium which lives in a symbiotic relationship with nematodes.
The tiny worms enter insect larvae through natural openings, where they proceed to "cough up" the bacteria, so to speak. Bacterial toxins produced by the light-emitting bacteria kill the insect larvae (see photo), thus creating a larger reservoir of nourishment for the proliferation of nematodes and bacteria. For this reason, the worms and their bacteria are often used as biogenic insecticides.
Photorhabdus luminescens produces various toxins which form large toxin complexes (Tc proteins). The biologically active complex consists of the three components TcA, TcB, and TcC. Until now, scientists have not succeeded in describing the enzymatic activity or the mode of action of these toxins.
A team of researchers at the University of Freiburg led by Prof. Dr. Dr. Klaus Aktories and Prof. Dr. Gudula Schmidt investigated the effects of the toxins on insect and mammal cells together with researchers from the company Dow AgroSciences (USA) and Prof. Dr. Hans Georg Mannherz (University of Bochum and Max Planck Institute for Molecular Physiology in Dortmund). They were able to demonstrate that the biological activity is localized in the TcC components TccC3 and TccC5.
The two toxin components are enzymes which inhibit essential defense mechanisms of immune cells, such as the intake and elimination of bacteria. The toxins act on the target cells of the insect larvae in two different ways: TccC3 modifies the cytoskeleton protein actin directly at the amino acid threonine-148 by adding ADP-ribose. This leads to the elimination of a regulator of actin (thymosin-β4), resulting in a greatly increased polymerization of the cytoskeleton. The second toxin, TccC5, effects changes in Rho proteins, the switching proteins for the regulation of the actin cytoskeleton. These regulators are switched on and off again in the cell. TccC5 modifies the switch at the amino acid glutamine-63, also by adding ADP-ribose, and prevents it from being switched off. The permanently active Rho protein then promotes the polymerization of actin.
Together, the two toxins lead to a strong aggregation and cluster building in the actin cytoskeleton which is incompatible with normal cellular function and immune defense. In order to enter the insect cells, the toxins TccC3 and TccC5 need TcA as it builds the pores in the host cells they likely use to penetrate into the inside of the cell.
Tc proteins have also been identified in human pathogenic bacteria such as Yersinia pseudotuberculosis and Yersinia pestis. A full explanation of the molecular mechanisms of the prototypical tc proteins is thus of paramount importance for reaching an understanding of other tc proteins from insecticides and human pathogenic bacteria.
- Alexander E. Lang, Gudula Schmidt, Andreas Schlosser, Timothy D. Hey, Ignacio M. Larrinua, Joel J. Sheets, Hans G. Mannherz, and Klaus Aktories. Photorhabdus luminescens Toxins ADP-Ribosylate Actin and RhoA to Force Actin Clustering. Science, 2010; 327 (5969): 1139 DOI: 10.1126/science.1184557
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