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Functional dissection of the retrograde Shiga toxin trafficking inhibitor Retro-2

Abstract : 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.
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https://hal.inrae.fr/hal-03321166
Contributor : Camille Serva <>
Submitted on : Tuesday, August 17, 2021 - 10:54:29 AM
Last modification on : Thursday, August 19, 2021 - 3:26:31 AM

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Alison Forrester, Stefan Rathjen, Maria Daniela Garcia-Castillo, Collin Bachert, Audrey Couhert, et al.. Functional dissection of the retrograde Shiga toxin trafficking inhibitor Retro-2. Nature Chemical Biology, Nature Publishing Group, 2020, 16 (3), pp.327-336. ⟨10.1038/s41589-020-0474-4⟩. ⟨hal-03321166⟩

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