期刊
NATURE CHEMICAL BIOLOGY
卷 16, 期 3, 页码 327-+出版社
NATURE RESEARCH
DOI: 10.1038/s41589-020-0474-4
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资金
- Agence Nationale pour la Recherche [ANR-11-BSV2-0018, ANR-14-CE16-0004-03, ANR-19-CE13-0001-01]
- Human Frontier Science Program [RGP0029-2014]
- European Research Council [340485]
- Swedish Research Council [K2015-99X-22877-01-6]
- Joint Ministerial Program of R&D against CBRNE Risks
- Ile de France Region DIM Malinf initiative [140101]
- Region Ile-de-France
- Fondation pour la Recherche Medicale
- CEA
- Agence Nationale de la Recherche (ANR) [ANR-14-CE16-0004, ANR-19-CE13-0001, ANR-11-BSV2-0018] Funding Source: Agence Nationale de la Recherche (ANR)
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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