Open AccessFunctional dissection of the retrograde Shiga toxin trafficking inhibitor Retro-2
Author(s) -
Alison Forrester,
Stefan J. Rathjen,
María García-Castillo,
Collin Bachert,
Audrey Couhert,
Livia Tepshi,
Sylvain Pichard,
Jennifer Martinez,
Mathilde Munier,
Raphaël Sierocki,
HenriFrançois Renard,
César Augusto Valades-Cruz,
Florent Dingli,
Damarys Loew,
Christophe Lamaze,
JeanChristophe Cintrat,
Adam D. Linstedt,
Daniel Gillet,
Julien Barbier,
Ludger Johannes
Publication year - 2020
Publication title -
nature chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.412
H-Index - 216
eISSN - 1552-4469
pISSN - 1552-4450
DOI - 10.1038/s41589-020-0474-4
Subject(s) - endosome , syntaxin , golgi apparatus , endoplasmic reticulum , microbiology and biotechnology , syntaxin 3 , retromer , transport protein , shiga toxin , chaperone (clinical) , axoplasmic transport , chemistry , biology , membrane protein , biochemistry , gene , intracellular , membrane , escherichia coli , medicine , pathology
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.