TY - JOUR
T1 - Functional dissection of the retrograde Shiga toxin trafficking inhibitor Retro-2
AU - Forrester, Alison
AU - Rathjen, Stefan J.
AU - Daniela Garcia-Castillo, Maria
AU - Bachert, Collin
AU - Couhert, Audrey
AU - Tepshi, Livia
AU - Pichard, Sylvain
AU - Martinez, Jennifer
AU - Munier, Mathilde
AU - Sierocki, Raphael
AU - Renard, Henri François
AU - Augusto Valades-Cruz, César
AU - Dingli, Florent
AU - Loew, Damarys
AU - Lamaze, Christophe
AU - Cintrat, Jean Christophe
AU - Linstedt, Adam D.
AU - Gillet, Daniel
AU - Barbier, Julien
AU - Johannes, Ludger
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85079815125&partnerID=8YFLogxK
U2 - 10.1038/s41589-020-0474-4
DO - 10.1038/s41589-020-0474-4
M3 - Article
C2 - 32080624
AN - SCOPUS:85079815125
SN - 1552-4450
VL - 16
SP - 327
EP - 336
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 3
ER -