Functional dissection of the retrograde Shiga toxin trafficking inhibitor Retro-2
(2020) Nature Chemical Biology — Vol. 16, n° 3, p. 327-336 (2020)
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- 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. In 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 endosomes to the Golgi. We thereby identify Sec16A as a druggable target, and provide evidence for a non-SNARE function for syntaxin-5 in interaction with the GPP130.
- Affiliations
Institut Curie
Citations
Forrester, A., Rathjen, S., Garcia-Castillo, M. D., Bachert, C., Couhert, A., Tepshi, L., Pichard, S., Martinez, J., Munier, M., Sierocki, R., Renard, H.-F., Valades-Cruz, C. A., Dingli, F., & et al. (2020). Functional dissection of the retrograde Shiga toxin trafficking inhibitor Retro-2. Nature Chemical Biology, 16(3), 327-336. https://hdl.handle.net/2078.5/94664 (Original work published 2020)