DAP1, a Negative Regulator of Autophagy, Controls SubAB-Mediated Apoptosis and Autophagy

Yahiro, Kinnosuke; Tsutsuki, Hiroyasu; Ogura, Kohei; Moss, Joel; Noda, Masatoshi

doi:10.1128/iai.02213-14

Cited by 34 publications

(30 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This effect also was observed when much lower concentrations of SubA 1 were delivered into cells via the SubB 1 transport subunit, and comparable results were reported earlier by other groups for the SubAB 1 cytotoxin (37)(38)(39)(40). This finding explains the observed alterations in cell morphology and the reduced number of viable cells after incubation with high concentrations of SubA 1 in the absence of SubB 1 .…”

Section: Discussionsupporting

confidence: 78%

Cytotoxic and Apoptotic Effects of Recombinant Subtilase Cytotoxin Variants of Shiga Toxin-Producing Escherichia coli

et al. 2015

View full text Add to dashboard Cite

In this study, the cytotoxicity of the recently described subtilase variant SubAB 2-2 of Shiga toxin-producing Escherichia coli was determined and compared to the plasmid-encoded SubAB 1 and the chromosome-encoded SubAB 2-1 variant. The genes for the respective enzymatic active (A) subunits and binding (B) subunits of the subtilase toxins were amplified and cloned. The recombinant toxin subunits were expressed and purified. Shiga toxin-producing Escherichia coli (STEC) strains are zoonotic bacterial pathogens causing a variety of symptoms in humans, ranging from relatively mild forms, such as diarrhea, to hemorrhagic colitis and the life-threatening hemolytic-uremic syndrome (HUS) (1). Besides Shiga toxin, the best-characterized pathogenicity factor for the development of serious diseases is the locus of enterocyte effacement (LEE), encoding a type III secretion system and associated effector proteins (2, 3). Other pathogenicity factors can be involved in the development of human disease (4, 5). An example is the subtilase cytotoxin (SubAB), which is located on a 163-kb plasmid of STEC E. coli O113:H21 strain 98NK2 (6). This strain was isolated from a case of HUS in the south of Australia. The subtilase cytotoxin was shown to cause HUS-like symptoms in mice and apoptosis in human epithelial cells (7-9). Subtilase cytotoxin genes were detected in a variety of LEE-negative STEC strains of human, ovine, and game origin (10-14). Furthermore, strains from human origin were shown to cause symptoms in humans ranging from watery diarrhea to fully developed HUS (15, 16).The SubAB toxin is a typical AB 5 toxin, composed of an enzymatically active A subunit (SubA) and a B pentamer (SubB), which mediates the uptake of the toxin into target cells by binding to a specific surface sialic acid, namely, N-glycolylneuraminic acid (Neu5Gc) (17). Neu5Gc is present in most mammals but is not synthesized by human cells due to a 92-bp deletion in the cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) gene (18). However, it was shown that human cells are able to incorporate Neu5Gc from external sources (19). Inside the eukaryotic cell, the enzymatic active A subunit acts as a subtilisinlike serine protease. SubA cleaves the cellular endoplasmic reticulum chaperone GRP78/BiP at an L-L motif on position 416 between the N-terminal ATPase domain and the C-terminal protein binding domain (20). This highly specific protease activity is unique within AB 5 toxins and leads to the accumulation of unfolded proteins in the endoplasmic reticulum. This accumulation induces the unfolded protein response (UPR), which in the end results in the death of the affected cell (21). Yahiro and coworkers demonstrated that binding of SubAB to one of four different cell surface receptors, namely, NG2, hepatocyte growth factor receptor (Met), L1 cell adhesion molecule (CAM), and ß1 integrin (ITG), induces signals which also result in apoptosis of HeLa cells without internalization of SubAB (22). However, the underlying mechanism is not completely u...

show abstract

Section: Discussionsupporting

confidence: 78%

Cytotoxic and Apoptotic Effects of Recombinant Subtilase Cytotoxin Variants of Shiga Toxin-Producing Escherichia coli

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Despite analyses of several aspects of the biochemical processes involved in the functionality of SubAB and its consequences on the target cells, aspects of the regulation of SubAB expression itself are still unvetted [ 135 , 136 ]. One hypothesis is that the expression is triggered based on the position in the genome.…”

Section: Toxins Of Lee-negative Stecmentioning

confidence: 99%

Toxins of Locus of Enterocyte Effacement-Negative Shiga Toxin-Producing Escherichia coli

Krause

Barth

Schmidt

2018

Toxins

View full text Add to dashboard Cite

Studies on Shiga toxin-producing Escherichia coli (STEC) typically examine and classify the virulence gene profiles based on genomic analyses. Among the screened strains, a subgroup of STEC which lacks the locus of enterocyte effacement (LEE) has frequently been identified. This raises the question about the level of pathogenicity of such strains. This review focuses on the advantages and disadvantages of the standard screening procedures in virulence profiling and summarizes the current knowledge concerning the function and regulation of toxins encoded by LEE-negative STEC. Although LEE-negative STEC usually come across as food isolates, which rarely cause infections in humans, some serotypes have been implicated in human diseases. In particular, the LEE-negative E. coli O104:H4 German outbreak strain from 2011 and the Australian O113:H21 strain isolated from a HUS patient attracted attention. Moreover, the LEE-negative STEC O113:H21 strain TS18/08 that was isolated from minced meat is remarkable in that it not only encodes multiple toxins, but in fact expresses three different toxins simultaneously. Their characterization contributes to understanding the virulence of the LEE-negative STEC.

show abstract

“…Furthermore, Halder et al reported that the Helicobacter pylori produced HP0175, a peptidyl-prolyl cis-trans isomerase, activates the PERK arm consequently leading to production of ATF4 and CHOP which both induce the expression of autophagy-related genes [ 23 ]. In contrast, SubAB-triggered PERK activation suppresses autophagy [ 24 ]. Thus, PERK-dependent autophagy induction seems to be insult dependent.…”

Section: The Role Of Individual Er Stress Marker Activationmentioning

confidence: 99%

Diverse roles of endoplasmic reticulum stress sensors in bacterial infection

et al. 2016

View full text Add to dashboard Cite

Bacterial infection often leads to cellular damage, primarily marked by loss of cellular integrity and cell death. However, in recent years, it is being increasingly recognized that, in individual cells, there are graded responses collectively termed cell-autonomous defense mechanisms that induce cellular processes designed to limit cell damage, enable repair, and eliminate bacteria. Many of these responses are triggered not by detection of a particular bacterial effector or ligand but rather by their effects on key cellular processes and changes in homeostasis induced by microbial effectors when recognized. These in turn lead to a decrease in essential cellular functions such as protein translation or mitochondrial respiration and the induction of innate immune responses that may be specific to the cellular deficit induced. These processes are often associated with specific cell compartments, e.g., the endoplasmic reticulum (ER). Under non-infection conditions, these systems are generally involved in sensing cellular stress and in inducing and orchestrating the subsequent cellular response. Thus, perturbations of ER homeostasis result in accumulation of unfolded proteins which are detected by ER stress sensors in order to restore the normal condition. The ER is also important during bacterial infection, and bacterial effectors that activate the ER stress sensors have been discovered. Increasing evidence now indicate that bacteria have evolved strategies to differentially activate different arms of ER stress sensors resulting in specific host cell response. In this review, we will describe the mechanisms used by bacteria to activate the ER stress sensors and discuss their role during infection.

show abstract

DAP1, a Negative Regulator of Autophagy, Controls SubAB-Mediated Apoptosis and Autophagy

Cited by 34 publications

References 60 publications

Cytotoxic and Apoptotic Effects of Recombinant Subtilase Cytotoxin Variants of Shiga Toxin-Producing Escherichia coli

Cytotoxic and Apoptotic Effects of Recombinant Subtilase Cytotoxin Variants of Shiga Toxin-Producing Escherichia coli

Toxins of Locus of Enterocyte Effacement-Negative Shiga Toxin-Producing Escherichia coli

Diverse roles of endoplasmic reticulum stress sensors in bacterial infection

Contact Info

Product

Resources

About