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Shiga Toxins as Multi-Functional Proteins: Induction of Host Cellular Stress Responses, Role in Pathogenesis and Therapeutic Applications - PubMed

  • ️Fri Jan 01 2016

Review

Shiga Toxins as Multi-Functional Proteins: Induction of Host Cellular Stress Responses, Role in Pathogenesis and Therapeutic Applications

Moo-Seung Lee et al. Toxins (Basel). 2016.

Abstract

Shiga toxins (Stxs) produced by Shiga toxin-producing bacteria Shigella dysenteriae serotype 1 and select serotypes of Escherichia coli are primary virulence factors in the pathogenesis of hemorrhagic colitis progressing to potentially fatal systemic complications, such as hemolytic uremic syndrome and central nervous system abnormalities. Current therapeutic options to treat patients infected with toxin-producing bacteria are limited. The structures of Stxs, toxin-receptor binding, intracellular transport and the mode of action of the toxins have been well defined. However, in the last decade, numerous studies have demonstrated that in addition to being potent protein synthesis inhibitors, Stxs are also multifunctional proteins capable of activating multiple cell stress signaling pathways, which may result in apoptosis, autophagy or activation of the innate immune response. Here, we briefly present the current understanding of Stx-activated signaling pathways and provide a concise review of therapeutic applications to target tumors by engineering the toxins.

Keywords: Shiga toxin type 1 and 2; Shiga toxin-producing Escherichia coli; Shiga toxins; cancer therapeutics; hemolytic uremic syndrome; signaling pathways.

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Figures

Figure 1
Figure 1

Crystal structure of Shiga toxin. (A) Shiga toxin type 1 (PDB #1DM0); (B) Shiga toxin type 2 (PDB #1R4P); (C) Shiga toxin 1 B-subunit with Gb3 receptor (PDB #1BOS); (D) Shiga toxin 2 B-subunit with Gb3 receptor (PDB #1R4P, deletion of A-subunit). In (A,B), A-subunits are shown in dark blue, with B-subunits shown in different colors; in (C,D), individual B-subunits are shown in different colors. PDB files of all structures were obtained from RCSB PDB (Research Collaboratory for Structural Bioinformatics Protein Data Base,

www.rcsb.org

) and compiled PDB files with Chimera 1.10.2 (UCSF Chimera,

www.cgl.ucsf.edu/chimera

).

Figure 2
Figure 2

Host cell responses (ribotoxic stress, ER stress, inflammation, autophagy and apoptosis) induced by Stxs, following the membrane invagination-mediated endocytosis via toxin receptor Gb3 on the cell surface.

Figure 3
Figure 3

Schematic diagram of StxB-anticancer agent conjugates, imaging molecules (A) and chemical drug molecules (B) [184].

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