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Ricin can be isolated from the seeds of the castor bean plant (Ricinus communis). It belongs to the ribosome-inactivating protein (RIP) family of toxins classified as a bio-threat agent due to its high toxicity, stability and availability. Ricin is a typical A-B toxin consisting of a single enzymatic A subunit (RTA) and a binding B subunit (RTB) joined by a single disulfide bond. RTA possesses an RNA N-glycosidase activity; it cleaves ribosomal RNA leading to the inhibition of protein synthesis. However, the mechanism of ricin-mediated cell death is quite complex, as a growing number of studies demonstrate that the inhibition of protein synthesis is not always correlated with long term ricin toxicity. To exert its cytotoxic effect, ricin A-chain has to be transported to the cytosol of the host cell. This translocation is preceded by endocytic uptake of the toxin and retrograde traffic through the trans-Golgi network (TGN) and the endoplasmic reticulum (ER). In this article, we describe intracellular trafficking of ricin with particular emphasis on host cell factors that facilitate this transport and contribute to ricin cytotoxicity in mammalian and yeast cells. The current understanding of the mechanisms of ricin-mediated cell death is discussed as well. We also comment on recent reports presenting medical applications for ricin and progress associated with the development of vaccines against this toxin.
Natalia Sowa-Rogozińska; Hanna Sominka; Jowita Nowakowska-Gołacka; Kirsten Sandvig; Monika Słomińska-Wojewódzka. Intracellular Transport and Cytotoxicity of the Protein Toxin Ricin. Toxins 2019, 11, 350 .
AMA StyleNatalia Sowa-Rogozińska, Hanna Sominka, Jowita Nowakowska-Gołacka, Kirsten Sandvig, Monika Słomińska-Wojewódzka. Intracellular Transport and Cytotoxicity of the Protein Toxin Ricin. Toxins. 2019; 11 (6):350.
Chicago/Turabian StyleNatalia Sowa-Rogozińska; Hanna Sominka; Jowita Nowakowska-Gołacka; Kirsten Sandvig; Monika Słomińska-Wojewódzka. 2019. "Intracellular Transport and Cytotoxicity of the Protein Toxin Ricin." Toxins 11, no. 6: 350.
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.
Jowita Nowakowska-Gołacka; Hanna Sominka; Natalia Sowa-Rogozińska; Monika Słomińska-Wojewódzka. Toxins Utilize the Endoplasmic Reticulum-Associated Protein Degradation Pathway in Their Intoxication Process. International Journal of Molecular Sciences 2019, 20, 1307 .
AMA StyleJowita Nowakowska-Gołacka, Hanna Sominka, Natalia Sowa-Rogozińska, Monika Słomińska-Wojewódzka. Toxins Utilize the Endoplasmic Reticulum-Associated Protein Degradation Pathway in Their Intoxication Process. International Journal of Molecular Sciences. 2019; 20 (6):1307.
Chicago/Turabian StyleJowita Nowakowska-Gołacka; Hanna Sominka; Natalia Sowa-Rogozińska; Monika Słomińska-Wojewódzka. 2019. "Toxins Utilize the Endoplasmic Reticulum-Associated Protein Degradation Pathway in Their Intoxication Process." International Journal of Molecular Sciences 20, no. 6: 1307.