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Scientific result | Health ＆ life sciences | CBRN-E threats
Researchers from SIMoS, SCBM and Institut Curie, in collaboration with Carnegie Mellon University (USA), have identified the intracellular target and the mechanism of action of Retro-2, a broad-spectrum inhibitor of intracellular toxins and pathogens. They are now working on the design of an effective drug in the event of a bioterrorist attack or a health crisis.
The retrograde transport inhibitor Retro-2 has a protective effect on cells and in mice against Shiga-like toxins and ricin. Retro-2 causes toxin accumulation in early endosomes and relocalization of the Golgi SNARE protein syntaxin-5 to the endoplasmic reticulum. The molecular mechanisms by which this is achieved remain unknown. Here, we show that Retro-2 targets the endoplasmic reticulum exit site component Sec16A, affecting anterograde transport of syntaxin-5 from the endoplasmic reticulum to the Golgi. The formation of canonical SNARE complexes involving syntaxin-5 is not affected in Retro-2-treated cells. By contrast, the interaction of syntaxin-5 with a newly discovered binding partner, the retrograde trafficking chaperone GPP130, is abolished, and we show that GPP130 must indeed bind to syntaxin-5 to drive Shiga toxin transport from the endosomes to the Golgi. We therefore identify Sec16A as a druggable target and provide evidence for a non-SNARE function for syntaxin-5 in interaction with GPP130.See the CEA press release of February, 21, 2020
A Forrester, SJ Rathjen, MD Garcia-Castillo, C Bachert, A Couhert, L Tepshi, S Pichard, J Martinez, M Munier, R Sierocki, HF Renard, CA Valades-Cruz, F Dingli, D Loew, C Lamaze, JC Cintrat, AD Linstedt, D Gillet, J Barbier, L Johannes (2020) Functional dissection of the retrograde Shiga toxin trafficking inhibitor Retro-2. Nat.Chem.Biol, in press
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.