title: Manganese blocks intracellular trafficking of Shiga toxin and protects against Shiga toxicosis.
abstract: Infections with Shiga toxin (STx)-producing bacteria cause more than a million deaths each year and have no definitive treatment. To exert its cytotoxic effect, STx invades cells through retrograde membrane trafficking, escaping the lysosomal degradative pathway. We found that the widely available metal manganese (Mn(2+)) blocked endosome-to-Golgi trafficking of STx and caused its degradation in lysosomes. Mn(2+) targeted the cycling Golgi protein GPP130, which STx bound in control cells during sorting into Golgi-directed endosomal tubules that bypass lysosomes. In tissue culture cells, treatment with Mn(2+) yielded a protection factor of 3800 against STx-induced cell death. Furthermore, mice injected with nontoxic doses of Mn(2+) were completely resistant to a lethal STx challenge. Thus, Mn(2+) may represent a low-cost therapeutic agent for the treatment of STx infections.
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
authors.forename: Somshuvra
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Adam D
authors.initials: AD
authors.lastname: Linstedt
mesh_terms: D000818:Animals; D016923:Cell Death; D002462:Cell Membrane / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007928:Lethal Dose 50; D008247:Lysosomes / Q000378:metabolism*; D008345:Manganese / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D022622:Shiga Toxin 1 / Q000378:metabolism* / Q000633:toxicity*; D022603:Shiga Toxins / Q000378:metabolism* / Q000633:toxicity*; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: C107340:GOLIM4 protein, human; D022622:Shiga Toxin 1; D022603:Shiga Toxins; D033921:Vesicular Transport Proteins; C077239:stxB toxin; D008345:Manganese