Abstract
Several bacterial and plant AB-toxins are delivered by retrograde vesicular transport to the endoplasmic reticulum (ER), where the enzymatically active A subunit is disassembled from the holotoxin and transported to the cytosol. In this process, toxins subvert the ER-associated degradation (ERAD) pathway. ERAD is an important part of cellular regulatory mechanism that targets misfolded proteins to the ER channels, prior to their retrotranslocation to the cytosol, ubiquitination and subsequent degradation by a protein-degrading complex, the proteasome. In this article, we present an overview of current understanding of the ERAD-dependent transport of AB-toxins to the cytosol. We describe important components of ERAD and discuss their significance for toxin transport. Toxin recognition and disassembly in the ER, transport through ER translocons and finally cytosolic events that instead of overall proteasomal degradation provide proper folding and cytotoxic activity of AB-toxins are discussed as well. We also comment on recent reports presenting medical applications for toxin transport through the ER channels.
Highlights
Endoplasmic reticulum (ER) is a major cellular protein folding compartment that regulates biosynthesis, assembly and trafficking of most secretory and membrane proteins [1]
Besides oxidoreductases that belong to the protein disulphide isomerase family [88], which like PDI can discriminate between substrates based on their degree of folding [89], the endoplasmic reticulum (ER) contains specific molecular chaperones, folding enzymes and quality control factors that promote correct folding of newly synthesized polypeptides and ensure that only properly folded and assembled proteins are transported through the secretory pathway
These two scopes were not developed independently, they were connected with each other in many aspects. This happened because toxin transport from the ER to the cytosol by ER-associated degradation (ERAD) is a crucial part of toxin intracellular routing that significantly contributes to regulation of their toxicity
Summary
Endoplasmic reticulum (ER) is a major cellular protein folding compartment that regulates biosynthesis, assembly and trafficking of most secretory and membrane proteins [1]. Active CTA1 of cholera toxin induces ADP-ribosylation of the Gs alpha subunit (Gαs) proteins using NAD. The Pseudomonas exotoxin A (Figure 2D) and ricin (Figure 2C) belong to the two-component AB-toxin family, composed of an A domain with enzymatic activity and a B domain serving as the cell binding subunit [38,39]. All of the described toxins have different intracellular targets and exert very diverse effects on eukaryotic cells They induce overall cytotoxicity, cell apoptosis and tissue damage or generate. They induce overall cytotoxicity, cell apoptosis and tissue damage or generate more subtle alternations in the host through changes in the cell cycle progression. We describe how regulated toxin transport across the ER membrane can rescue misfolded mutant proteins from degradation to increase their cellular function
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