Enteropathogenic
            <i>Escherichia coli</i>
            regulates host-cell mitochondrial morphology

Roxas, Jennifer Lising; Ramamurthy, Shylaja; Cocchi, Katie; Rutins, Ilga; Harishankar, Anusha; Agellon, Al; Wilbur, J. Scott; Sylejmani, Gresa; Vedantam, Gayatri; Viswanathan, V. K.

doi:10.1080/19490976.2022.2143224

Cited by 8 publications

(7 citation statements)

References 78 publications

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“…In these studies, it has been shown that infection with EPEC-Δ espZ , but not with EPEC-Δ espZ /pEspZ, diminished the mitochondrial membrane potential, an activity that can be promoted by mitochondrial cell death. Additional studies have shown that ectopically expressed EspZ indeed colocalizes with mitochondrial markers ( 17 , 20 ). However, the localization of translocated EspZ vis-à-vis mitochondria has not been studied.…”

Section: Resultsmentioning

confidence: 93%

“…Several studies have related the capability of EspZ to protect against host cell death to its ability to target host mitochondria. Those include (i) interactions of EspZ with the mitochondrial translocator (e.g., TIM17b) ( 17 ), (ii) targeting mitochondrial proteins which control mitochondrial integrity (e.g., FIS1) ( 20 ), and (iii) blocking the translocation of pro-death effectors, such as EspF and Map ( 11 , 24 , 29 ). However, EspZ has been localized to mitochondria only when the effector was ectopically expressed in mammalian cells, leaving the mitochondrial localization of the translocated effector, which is the more physiologically relevant form of the effector, unexplored.…”

Section: Discussionmentioning

confidence: 99%

“…A prominent hallmark of EspZ is the capacity to inhibit epithelial cell death ( 13 , 17 , 18 ). This has been suggested to occur by several mechanisms, including the ability to block the type III secretion of pro-death effectors (e.g., EspF and Map), the capability to interact with host pro-survival protein CD98 ( 19 ), and the capability to interact and alter the morphological and functional properties of host mitochondria ( 17 , 20 ). However, these studies tested the ectopically expressed effector, which could be physiologically less relevant than the translocated one.…”

Section: Introductionmentioning

confidence: 99%

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Topology and function of translocated EspZ

Haritan,

Bouman,

Nandi

et al. 2023

mBio

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EspZ and Tir are essential virulence effectors of enteropathogenic Escherichia coli (EPEC). EspZ, the second translocated effector, has been suggested to antagonize host cell death induced by the first translocated effector, Tir (translocated intimin receptor). Another characteristic of EspZ is its localization to host mitochondria. However, studies that explored the mitochondrial localization of EspZ have examined the ectopically expressed effector and not the more physiologically relevant translocated effector. Here, we confirmed the membrane topology of translocated EspZ at infection sites and the involvement of Tir in confining its localization to these sites. Unlike the ectopically expressed EspZ, the translocated EspZ did not colocalize with mitochondrial markers. Moreover, no correlation has been between the capacity of ectopically expressed EspZ to target mitochondria and the ability of translocated EspZ to protect against cell death. Translocated EspZ may have to some extent diminished F-actin pedestal formation induced by Tir but has a marked effect on protecting against host cell death and on promoting host colonization by the bacteria. Taken together, our results suggest that EspZ plays an essential role in facilitating bacterial colonization, likely by antagonizing cell death mediated by Tir at the onset of bacterial infection. This activity of EspZ, which occurs by targeting host membrane components at infection sites, and not mitochondria, may contribute to successful bacterial colonization of the infected intestine. IMPORTANCE EPEC is an important human pathogen that causes acute infantile diarrhea. EspZ is an essential virulence effector protein translocated from the bacterium into the host cells. Detailed knowledge of its mechanisms of action is, therefore, critical for better understanding the EPEC disease. We show that Tir, the first translocated effector, confines the localization of EspZ, the second translocated effector, to infection sites. This activity is important for antagonizing the pro-cell death activity conferred by Tir. Moreover, we show that translocated EspZ leads to effective bacterial colonization of the host. Hence, our data suggest that translocated EspZ is essential because it confers host cell survival to allow bacterial colonization at an early stage of bacterial infection. It performs these activities by targeting host membrane components at infection sites. Identifying these targets is critical for elucidating the molecular mechanism underlying the EspZ activity and the EPEC disease.

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Section: Resultsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Topology and function of translocated EspZ

Haritan,

Bouman,

Nandi

et al. 2023

mBio

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“…For instance, in the early stages of enteropathogenic Escherichia coli (EPEC) infection, the bacterial effector EspZ interacts with mitochondrial fission protein 1 (FIS1) of host epithelial cells, a mitochondrial outer membrane protein that mediates mitochondrial fragmentation. 40 This interaction protects the mitochondrial fusion network and enhances host cell viability, benefitting EPEC colonization. In contrast, at the late stage of infection, EPEC stimulates mitochondrial fragmentation via an EspH-dependent increase in FIS1 levels and causes a loss in ΔΨ m , 40 leading to host cell death, which likely facilitates pathogen dispersal.…”

Section: Discussionmentioning

confidence: 99%

“… 40 This interaction protects the mitochondrial fusion network and enhances host cell viability, benefitting EPEC colonization. In contrast, at the late stage of infection, EPEC stimulates mitochondrial fragmentation via an EspH-dependent increase in FIS1 levels and causes a loss in ΔΨ m , 40 leading to host cell death, which likely facilitates pathogen dispersal. In this study, at the early stages of S .…”

Section: Discussionmentioning

confidence: 99%

Salmonella enterica serovar Typhimurium remodels mitochondrial dynamics of macrophages via the T3SS effector SipA to promote intracellular proliferation

Liu,

Zhao

et al. 2024

Gut Microbes

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Mitochondrial dynamics are critical in cellular energy production, metabolism, apoptosis, and immune responses. Pathogenic bacteria have evolved sophisticated mechanisms to manipulate host cells’ mitochondrial functions, facilitating their proliferation and dissemination. Salmonella enterica serovar Typhimurium ( S . Tm), an intracellular foodborne pathogen, causes diarrhea and exploits host macrophages for survival and replication. However, S . Tm-associated mitochondrial dynamics during macrophage infection remain poorly understood. In this study, we showed that within macrophages, S . Tm remodeled mitochondrial fragmentation to facilitate intracellular proliferation mediated by Salmonella invasion protein A (SipA), a type III secretion system effector encoded by Salmonella pathogenicity island 1. SipA directly targeted mitochondria via its N-terminal mitochondrial targeting sequence, preventing excessive fragmentation and the associated increase in mitochondrial reactive oxygen species, loss of mitochondrial membrane potential, and release of mitochondrial DNA and cytochrome c into the cytosol. Macrophage replication assays and animal experiments showed that mitochondria and SipA interact to facilitate intracellular replication and pathogenicity of S . Tm. Furthermore, we showed that SipA delayed mitochondrial fragmentation by indirectly inhibiting the recruitment of cytosolic dynamin-related protein 1, which mediates mitochondrial fragmentation. This study revealed a novel mechanism through which S . Tm manipulates host mitochondrial dynamics, providing insights into the molecular interplay that facilitates S . Tm adaptation within host macrophages.

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Attaching and effacing pathogens modulate host mitochondrial structure and function

Harishankar¹,

Viswanathan²

2023

International Review of Cell and Molecular Biology

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Enteropathogenic Escherichia coli regulates host-cell mitochondrial morphology

Cited by 8 publications

References 78 publications

Topology and function of translocated EspZ

Topology and function of translocated EspZ

Salmonella enterica serovar Typhimurium remodels mitochondrial dynamics of macrophages via the T3SS effector SipA to promote intracellular proliferation

Attaching and effacing pathogens modulate host mitochondrial structure and function

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