The Intracellular Journey of Shiga Toxins

Abstract

Abstract:The Shiga toxin family consists of Shiga toxin (Stx) that is produced as a virulence factor by Shigella dysenteriae, and the Shiga-like toxins produced by certain strains of enterohemorrhagic E. coli as well as by some other types of bacteria. Infection with bacteria producing these toxins is a threat to human health even in industrialized countries, as the initial diarrhea caused by the infection might be followed by a complication named hemolytic uremic syndrome. The Shiga toxins consist of a binding moiety that in most cases binds to the glycosphingolipid Gb3 on the surface of susceptible cells, and an A-moiety responsible for the toxic effect in the cytosol. In order to reach its cytosolic target, the toxin must be internalized and then transported via the retrograde pathway to the Golgi complex and further to the endoplasmic reticulum. From the endoplasmic reticulum the enzymatically active part of the A-moiety is translocated to the cytosol, and cellular protein synthesis is inhibited. Although the Shiga toxins are involved in disease, they may also be exploited for medical diagnosis and treatment. Interestingly, the toxin receptor, Gb3, has a limited expression in normal tissues, but is overexpressed in several types of cancer. Thus, the use of Shiga toxin, or the binding part of the toxin, has great potential in cancer diagnostics and treatment. Furthermore, studies of the various uptake mechanisms and intracellular transport pathways exploited by the toxins, provide important insight in basic cell biology processes.

Simulation Study of cDNA Dataset to Investigate Possible Association of Differentially Expressed Genes of Human THP1-Monocytic Cells in Cancer Progression Affected by Bacterial Shiga Toxins

“…After internalization, the toxins undergo retrograde intracellular flow to reach the endoplasmic reticulum (Sandvig et al, 2002 ). Importantly, the toxin receptor, Gb3, has a limited expression in normal tissues but is overexpressed in several types of cancer and besides apoptosis, may cause “apoptosis induced proliferation” (Torgersen et al, 2010 ). Stxs are cytotoxic proteins that enter the host cell via macropinosome and function as an N-glycosidase, cleave a specific adenine nucleobase from the 28S RNA of the 60S subunit of the ribosome, thereby halting host cell protein synthesis (Sandvig et al, 2010 ; Lukyanenko et al, 2011 ).…”

Toxin Instability and Its Role in Toxin Translocation from the Endoplasmic Reticulum to the Cytosol

“…Other AB toxins have no pore-forming capacity and must therefore utilize an existing protein-conducting channel in the host endomembrane system for A chain passage to the cytosol. The endoplasmic reticulum (ER) is the only endomembrane organelle with such a channel, so these toxins must travel by vesicle carriers from the endosomes to the ER before A chain translocation to the cytosol can occur ( Figure 1 ) [ 4 , 5 , 6 , 7 ]. This review will focus on the structural changes that accompany A chain movement from the ER to the cytosol.…”

“…Shiga toxin (Stx) is an AB 5 toxin that contains an enzymatic A1 subunit, an A2 linker, and a B homopentamer [ 7 ] ( Figure 2 d). Like Ctx, the A subunit of Stx is proteolytically nicked to generate a disulfide-linked A1/A2 heterodimer [ 45 , 46 ].…”

“…This arrangement protects the holotoxin-associated A subunit from extracellular or endosomal/lysosomal proteases likely to be encountered in the host environment [ 47 , 53 , 54 , 55 , 56 , 57 ]. In addition to stabilizing the A chain, the B subunit is responsible for adhesion to the surface of a target cell and subsequent vesicle-mediated toxin delivery to the ER [ 4 , 5 , 6 , 7 ]. Holotoxin disassembly in the ER allows the free A chain to assume a disordered conformation which engages the ERAD system for export to the cytosol.…”

Failure of Manganese to Protect from Shiga Toxin

“…Proper trafficking through the cell is essential to Stx toxicity. After endocytosis, the Stx holotoxin is trafficked from early endosomes to the Golgi apparatus and endoplasmic reticulum (ER) [9], [10]. In the ER, the enzymatic A-subunit separates from the holotoxin, is processed, and released into the cytosol where it inhibits protein synthesis by cleaving a conserved adenine in 28S ribosomal RNA [11].…”