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

Autor: Forrester A; Institut Curie, PSL Research University, Cellular and Chemical Biology unit, U1143 INSERM, UMR3666 CNRS, Endocytic Trafficking and Intracellular Delivery team, Paris, France., Rathjen SJ; Institut Curie, PSL Research University, Cellular and Chemical Biology unit, U1143 INSERM, UMR3666 CNRS, Endocytic Trafficking and Intracellular Delivery team, Paris, France., Daniela Garcia-Castillo M; Institut Curie, PSL Research University, Cellular and Chemical Biology unit, U1143 INSERM, UMR3666 CNRS, Endocytic Trafficking and Intracellular Delivery team, Paris, France., Bachert C; Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA., Couhert A; CEA, INRAE, Medicaments et Technologies pour la Sante (MTS), SCBM, Université Paris-Saclay, Gif-sur-Yvette, France., Tepshi L; CEA, INRAE, Medicaments et Technologies pour la Sante (MTS), SIMoS, Université Paris-Saclay, Gif-sur-Yvette, France., Pichard S; CEA, INRAE, Medicaments et Technologies pour la Sante (MTS), SIMoS, Université Paris-Saclay, Gif-sur-Yvette, France., Martinez J; CEA, INRAE, Medicaments et Technologies pour la Sante (MTS), SIMoS, Université Paris-Saclay, Gif-sur-Yvette, France., Munier M; CEA, INRAE, Medicaments et Technologies pour la Sante (MTS), SCBM, Université Paris-Saclay, Gif-sur-Yvette, France., Sierocki R; CEA, INRAE, Medicaments et Technologies pour la Sante (MTS), SIMoS, Université Paris-Saclay, Gif-sur-Yvette, France., Renard HF; Institut Curie, PSL Research University, Cellular and Chemical Biology unit, U1143 INSERM, UMR3666 CNRS, Endocytic Trafficking and Intracellular Delivery team, Paris, France., Augusto Valades-Cruz C; Institut Curie, PSL Research University, Cellular and Chemical Biology unit, U1143 INSERM, UMR3666 CNRS, Endocytic Trafficking and Intracellular Delivery team, Paris, France., Dingli F; Institut Curie, Centre de Recherche, PSL Research University, Laboratoire de Spectrométrie de Masse Protéomique, Paris, France., Loew D; Institut Curie, Centre de Recherche, PSL Research University, Laboratoire de Spectrométrie de Masse Protéomique, Paris, France., Lamaze C; Institut Curie, PSL Research University, Cellular and Chemical Biology Unit, U1143 INSERM, UMR3666 CNRS, Membrane Dynamics and Mechanics of Intracellular Signaling team, Paris, France., Cintrat JC; CEA, INRAE, Medicaments et Technologies pour la Sante (MTS), SCBM, Université Paris-Saclay, Gif-sur-Yvette, France., Linstedt AD; Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA., Gillet D; CEA, INRAE, Medicaments et Technologies pour la Sante (MTS), SIMoS, Université Paris-Saclay, Gif-sur-Yvette, France. daniel.gillet@cea.fr., Barbier J; CEA, INRAE, Medicaments et Technologies pour la Sante (MTS), SIMoS, Université Paris-Saclay, Gif-sur-Yvette, France., Johannes L; Institut Curie, PSL Research University, Cellular and Chemical Biology unit, U1143 INSERM, UMR3666 CNRS, Endocytic Trafficking and Intracellular Delivery team, Paris, France. ludger.johannes@curie.fr.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2020 Mar; Vol. 16 (3), pp. 327-336. Date of Electronic Publication: 2020 Feb 17.
DOI: 10.1038/s41589-020-0474-4
Abstrakt: 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.
Databáze: MEDLINE
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