Shiga toxin 1 interaction with enterocytes causes apical protein mistargeting through the depletion of intracellular galectin-3.
Shiga toxins (Stx) 1 and 2 are responsible for intestinal and systemic sequelae of infection by enterohemorrhagic Escherichia coli (EHEC). However, the mechanisms through which enterocytes are damaged remain unclear. While secondary damage from ischemia and inflammation are postulated mechanisms for all intestinal effects, little evidence excludes roles for more primary toxin effects on intestinal epithelial cells. We now document direct pathologic effects of Stx on intestinal epithelial cells. We study a well-characterized rabbit model of EHEC infection, intestinal tissue and stool samples from EHEC-infected patients, and T84 intestinal epithelial cells treated with Stx1. Toxin uptake by intestinal epithelial cells in vitro and in vivo causes galectin-3 depletion from enterocytes by increasing the apical galectin-3 secretion. This Shiga toxin-mediated galectin-3 depletion impairs trafficking of several brush border structural proteins and transporters, including villin, dipeptidyl peptidase IV, and the sodium-proton exchanger 2, a major colonic sodium absorptive protein. The mistargeting of proteins responsible for the absorptive function might be a key event in Stx1-induced diarrhea. These observations provide new evidence that human enterocytes are directly damaged by Stx1. Conceivably, depletion of galectin-3 from enterocytes and subsequent apical protein mistargeting might even provide a means whereby other pathogens might alter intestinal epithelial absorption and produce diarrhea.
Laiko
Marina
M
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Murtazina
Rakhilya
R
Malyukova
Irina
I
Zhu
Chengru
C
Boedeker
Edgar C
EC
Gutsal
Oksana
O
O'Malley
Robert
R
Cole
Robert N
RN
Tarr
Phillip I
PI
Murray
Karen F
KF
Kane
Anne
A
Donowitz
Mark
M
Kovbasnjuk
Olga
O
D000818:Animals; D002460:Cell Line; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D020895:Enterocytes / Q000187:drug effects* / Q000378:metabolism; D054324:Enterohemorrhagic Escherichia coli / Q000502:physiology; D004927:Escherichia coli Infections / Q000503:physiopathology*; D037502:Galectin 3 / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000503:physiopathology; D008840:Microfilament Proteins / Q000378:metabolism*; D008954:Models, Biological; D021381:Protein Transport; D011817:Rabbits; D011994:Recombinant Proteins / Q000235:genetics; D022622:Shiga Toxin 1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*
D037502:Galectin 3; D008840:Microfilament Proteins; D011994:Recombinant Proteins; C081517:SLC9A2 protein, human; D022622:Shiga Toxin 1; D017923:Sodium-Hydrogen Exchangers; C026615:villin; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4