Shiga toxin 1 induces apoptosis through the endoplasmic reticulum stress response in human monocytic cells

Abstract

SummaryShiga toxins (Stxs) expressed by the enteric pathogens Shigella dysenteriae 1 and enterohaemorrhagic Escherichia coli are potent protein synthesis inhibitors. Shiga toxins have also been shown to induce apoptosis in epithelial, endothelial and monocytic cells. The precise relationship between protein synthesis inhibition and induction of apoptosis is not known. We show that stimulation of the myelogenous leukaemia cell line THP-1 with purified Stx1 induced the endoplasmic reticulum (ER) stress response. Stx1 treatment increased activation of the ER stress sensors IRE1, PERK and ATF6. Toxin treatment increased expression of the transcriptional regulator CHOP and the death domain-containing receptor DR5 at mRNA and protein levels. Following Stx1 intoxication, levels of the survival factor Bcl-2 decreased, while secretion of the death-inducing ligand TRAIL increased. Stx1 enzymatic activity was required for optimal activation of PERK and ATF6, but not IRE1. ER stress elicited by Stx1 increased the release of Ca 2+ from ER stores and the activation of the protease calpain. Inhibition of calpain activity led to reductions in Stx1-induced cleavage of procaspase-8 and apoptosis. Collectively, these data suggest that Shiga toxins trigger monocytic cell apoptosis through the ER stress response, the increased expression of DR5 and TRAIL, and activation of caspase-8 via a calpaindependent mechanism.

Association of Shiga toxin glycosphingolipid receptors with membrane microdomains of toxin-sensitive lymphoid and myeloid cells

“…Gb3Cer-and Gb4Cer-negative Jurkat and HL-60 cell lines were resistant, whereas Raji (Gb3Cer-positive) and THP-1 cells (Gb3Cer-and Gb4Cer-positive) were susceptible to Stx2, as expected from toxin treatment studies of THP-1 cells performed by others (98)(99)(100). However, THP-1 cells exhibited a rather moderate but signifi cant susceptibility toward Stx2 when compared with resistant Jurkat and HL-60 cells, although a more pronounced cytotoxicity has been reported for THP-1 cells using Stx1 ( 101 ).…”

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

“…Therefore, the pathogen minimally employs Ank9 to invoke ER stress while also utilizing Ank4 to modulate the ensuing UPR and ERAD to bolster its growth. Other intracellular bacterial effectors, including Brucella species TcpB and Listeria monocytogenes listeriolysin O, and extracellular bacterial toxins, such as Vibrio cholerae cholera toxin and Escherichia coli subtilase and Shiga toxin 1, induce the UPR and/or ER morphological changes (10,(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71). To our knowledge, Ank4 stands unique as the only bacterial protein identified thus far that modulates ERAD.…”

Mechanisms and consequences of macrophage apoptosis in atherosclerosis

“…Thus, the triggering of apoptosis could actually be part of the innate host defense system to prevent chronic infection by these organisms. In this regard, there is evidence that intracellular organisms activate the UPR as a mechanism to support synthesis of pathogen proteins (41)(42)(43), and these organisms also display PAMPs that can activate scavenger receptors and TLRs. Most interestingly, in vitro studies have shown that macrophage apoptosis is associated with control of infection by M. tuberculosis (40), and genetic studies in mice have shown an association between resistance to infection by M. tuberculosis and induction of macrophage apoptosis (44).…”