RT Journal Article
SR Electronic
T1 Tamoxifen blocks retrograde trafficking of Shiga toxin 1 and 2 and protects against lethal toxicosis
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900439
DO 10.26508/lsa.201900439
VO 2
IS 3
A1 Andrey S Selyunin
A1 Steven Hutchens
A1 Stanton F McHardy
A1 Somshuvra Mukhopadhyay
YR 2019
UL https://www.life-science-alliance.org/content/2/3/e201900439.abstract
AB Shiga toxin 1 (STx1) and 2 (STx2), produced by Shiga toxin–producing Escherichia coli, cause lethal untreatable disease. The toxins invade cells via retrograde trafficking. Direct early endosome-to-Golgi transport allows the toxins to evade degradative late endosomes. Blocking toxin trafficking, particularly at the early endosome-to-Golgi step, is appealing, but transport mechanisms of the more disease-relevant STx2 are unclear. Using data from a genome-wide siRNA screen, we discovered that disruption of the fusion of late endosomes, but not autophagosomes, with lysosomes blocked the early endosome-to-Golgi transport of STx2. A subsequent screen of clinically approved lysosome-targeting drugs identified tamoxifen (TAM) to be a potent inhibitor of the trafficking and toxicity of STx1 and STx2 in cells. The protective effect was independent of estrogen receptors but dependent on the weak base property of TAM, which allowed TAM to increase endolysosomal pH and alter endosomal dynamics. Importantly, TAM treatment enhanced survival of mice injected with a lethal dose of STx1 or STx2. Thus, it may be possible to repurpose TAM for treating Shiga toxin–producing E. coli infections.