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Disruption of fas-fas ligand signaling, apoptosis, and innate immunity by bacterial pathogens.

Caulfield AJ, Lathem WW - PLoS Pathog. (2014)

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.

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Fas ligand (FasL, CD95L) is a type-II membrane protein within the tumor necrosis factor (TNF) superfamily of death receptors... FasL shares 25%–30% sequence homology with related family member proteins such as tumor necrosis factor alpha (TNFα) and TNF-related apoptosis-inducing ligand (TRAIL), with the most similarity present in the C-terminal homology ectodomain that extends into the extracellular space for receptor binding... The Fas-FasL interaction recruits the Fas-associated death domain adapter protein (FADD) via death domain binding, which interacts with dimerized procaspase-8 to form the death-inducing signaling complex (DISC)... Caspase-8 catalyzes its autoactivation, followed by the proteolytic conversion of downstream effector caspases such as caspase-3 and -7 into their mature forms... In models of pulmonary inflammation, these mice exhibit reduced airway epithelial cell apoptosis, cytokine secretion, neutrophil influx, and tissue damage... Similar results are obtained during knockdown of Fas by small interfering RNA (siRNA)... Through the extracellular degradation of FasL on the surface of effector cells, Pla prevents the induction of Fas-dependent caspase-3/7 activation in target cells, thereby actively manipulating host innate defense responses (Figure 1)... The conserved Yersinia T3SS effector protein YopJ (also known as YopP in Y. enterocolitica) has been shown to enhance apoptosis in vitro under artificial secretion conditions... During its evolutionary divergence from Y. pseudotuberculosis, however, Y. pestis acquired mutations within YopJ that reduce the efficiency of its translocation, which results in decreased caspase activation and diminished apoptotic activity... In the lungs, it is possible that cells injected and reprogrammed by the Yersinia T3SS may be recognized by the host and thus targeted for clearance via caspase-3/7-dependent mechanisms, with associated activation of the innate immune response... Indeed, injection of the T3SS effector YopK is known to stimulate apoptosis of pulmonary macrophages, and the inhibition of Fas-FasL signaling by Pla may therefore act to limit the recognition and clearance of these cells, resulting in an altered cytokine response in the lungs... GlcNAcylation of these proteins prevents death domain oligomerization and thus aborts apoptotic signaling downstream of the TNF family death receptors TNFR1, Fas, and TRAIL... Some pathogens actively promote host apoptosis, while others inhibit Fas-FasL signaling... As the role of apoptosis in modulating host defenses becomes more clear, it will be important to validate the use of cell death manipulators as therapeutics for each infection model, since apoptosis may be detrimental to the host under certain circumstances, such as during systemic bacterial sepsis... Continued investigation of the mechanisms by which pathogens manipulate apoptosis to alter host responses, via a combination of intracellular or extracellular activities on either effector cells or target cells, will provide insight for the development of future therapeutics.

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Disruption of Fas-FasL signaling by Pla of Y. pestis and NleB of EPEC.In response to bacterial infections, the host attempts to induce Fas/FasL-dependent cell apoptosis. During pneumonic plague, however, the Pla protease of Y. pestis directly cleaves FasL on effector cells to prevent the initiation of Fas signaling, blocking the activation of the initiator caspase-8, effector caspases -3 and -7, and cell death by apoptosis. As an alternative strategy during gastrointestinal infection, EPEC injects the type-III-secreted effector NleB into the cytoplasm of target cells, where it modifies FADD with N-acetylglucosamine to prevent death domain binding and downstream signaling following the engagement of Fas by FasL. While the mechanisms by which these bacteria target Fas-FasL signaling are distinct, the end result is the same: inhibition of apoptosis.
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ppat-1004252-g001: Disruption of Fas-FasL signaling by Pla of Y. pestis and NleB of EPEC.In response to bacterial infections, the host attempts to induce Fas/FasL-dependent cell apoptosis. During pneumonic plague, however, the Pla protease of Y. pestis directly cleaves FasL on effector cells to prevent the initiation of Fas signaling, blocking the activation of the initiator caspase-8, effector caspases -3 and -7, and cell death by apoptosis. As an alternative strategy during gastrointestinal infection, EPEC injects the type-III-secreted effector NleB into the cytoplasm of target cells, where it modifies FADD with N-acetylglucosamine to prevent death domain binding and downstream signaling following the engagement of Fas by FasL. While the mechanisms by which these bacteria target Fas-FasL signaling are distinct, the end result is the same: inhibition of apoptosis.

Mentions: Some bacterial pathogens have developed virulence strategies to alter apoptosis during infection. For instance, following inhalation, macrophages phagocytose Chlamydia pneumoniae as a normal host defense mechanism. To evade killing of infected macrophages and to enhance pathogenesis, C. pneumoniae blocks cytochrome C release by the cell, thus inhibiting apoptosis via the intrinsic pathway [23]. Similarly, the virulence factors SidF of Legionella pneumophila and AvrA of Salmonella Typhimurium suppress apoptosis by inhibiting Bcl2 family proteins and by blocking c-Jun N-terminal kinase (JNK) signaling, respectively [24], [25]. Recently, several studies have described previously unknown mechanisms by which two bacterial pathogens overcome cell death–mediated host defenses by directly targeting the Fas-FasL signaling pathway. Yersinia pestis, the causative agent of the disease plague, prevents Fas induction by cleaving and inactivating FasL on the surface of effector cells, while enteropathogenic Escherichia coli (EPEC), a cause of gastrointestinal infections, post-translationally modifies FADD within target cells to arrest Fas-induced apoptosis (Figure 1).


Disruption of fas-fas ligand signaling, apoptosis, and innate immunity by bacterial pathogens.

Caulfield AJ, Lathem WW - PLoS Pathog. (2014)

Disruption of Fas-FasL signaling by Pla of Y. pestis and NleB of EPEC.In response to bacterial infections, the host attempts to induce Fas/FasL-dependent cell apoptosis. During pneumonic plague, however, the Pla protease of Y. pestis directly cleaves FasL on effector cells to prevent the initiation of Fas signaling, blocking the activation of the initiator caspase-8, effector caspases -3 and -7, and cell death by apoptosis. As an alternative strategy during gastrointestinal infection, EPEC injects the type-III-secreted effector NleB into the cytoplasm of target cells, where it modifies FADD with N-acetylglucosamine to prevent death domain binding and downstream signaling following the engagement of Fas by FasL. While the mechanisms by which these bacteria target Fas-FasL signaling are distinct, the end result is the same: inhibition of apoptosis.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4125287&req=5

ppat-1004252-g001: Disruption of Fas-FasL signaling by Pla of Y. pestis and NleB of EPEC.In response to bacterial infections, the host attempts to induce Fas/FasL-dependent cell apoptosis. During pneumonic plague, however, the Pla protease of Y. pestis directly cleaves FasL on effector cells to prevent the initiation of Fas signaling, blocking the activation of the initiator caspase-8, effector caspases -3 and -7, and cell death by apoptosis. As an alternative strategy during gastrointestinal infection, EPEC injects the type-III-secreted effector NleB into the cytoplasm of target cells, where it modifies FADD with N-acetylglucosamine to prevent death domain binding and downstream signaling following the engagement of Fas by FasL. While the mechanisms by which these bacteria target Fas-FasL signaling are distinct, the end result is the same: inhibition of apoptosis.
Mentions: Some bacterial pathogens have developed virulence strategies to alter apoptosis during infection. For instance, following inhalation, macrophages phagocytose Chlamydia pneumoniae as a normal host defense mechanism. To evade killing of infected macrophages and to enhance pathogenesis, C. pneumoniae blocks cytochrome C release by the cell, thus inhibiting apoptosis via the intrinsic pathway [23]. Similarly, the virulence factors SidF of Legionella pneumophila and AvrA of Salmonella Typhimurium suppress apoptosis by inhibiting Bcl2 family proteins and by blocking c-Jun N-terminal kinase (JNK) signaling, respectively [24], [25]. Recently, several studies have described previously unknown mechanisms by which two bacterial pathogens overcome cell death–mediated host defenses by directly targeting the Fas-FasL signaling pathway. Yersinia pestis, the causative agent of the disease plague, prevents Fas induction by cleaving and inactivating FasL on the surface of effector cells, while enteropathogenic Escherichia coli (EPEC), a cause of gastrointestinal infections, post-translationally modifies FADD within target cells to arrest Fas-induced apoptosis (Figure 1).

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Fas ligand (FasL, CD95L) is a type-II membrane protein within the tumor necrosis factor (TNF) superfamily of death receptors... FasL shares 25%–30% sequence homology with related family member proteins such as tumor necrosis factor alpha (TNFα) and TNF-related apoptosis-inducing ligand (TRAIL), with the most similarity present in the C-terminal homology ectodomain that extends into the extracellular space for receptor binding... The Fas-FasL interaction recruits the Fas-associated death domain adapter protein (FADD) via death domain binding, which interacts with dimerized procaspase-8 to form the death-inducing signaling complex (DISC)... Caspase-8 catalyzes its autoactivation, followed by the proteolytic conversion of downstream effector caspases such as caspase-3 and -7 into their mature forms... In models of pulmonary inflammation, these mice exhibit reduced airway epithelial cell apoptosis, cytokine secretion, neutrophil influx, and tissue damage... Similar results are obtained during knockdown of Fas by small interfering RNA (siRNA)... Through the extracellular degradation of FasL on the surface of effector cells, Pla prevents the induction of Fas-dependent caspase-3/7 activation in target cells, thereby actively manipulating host innate defense responses (Figure 1)... The conserved Yersinia T3SS effector protein YopJ (also known as YopP in Y. enterocolitica) has been shown to enhance apoptosis in vitro under artificial secretion conditions... During its evolutionary divergence from Y. pseudotuberculosis, however, Y. pestis acquired mutations within YopJ that reduce the efficiency of its translocation, which results in decreased caspase activation and diminished apoptotic activity... In the lungs, it is possible that cells injected and reprogrammed by the Yersinia T3SS may be recognized by the host and thus targeted for clearance via caspase-3/7-dependent mechanisms, with associated activation of the innate immune response... Indeed, injection of the T3SS effector YopK is known to stimulate apoptosis of pulmonary macrophages, and the inhibition of Fas-FasL signaling by Pla may therefore act to limit the recognition and clearance of these cells, resulting in an altered cytokine response in the lungs... GlcNAcylation of these proteins prevents death domain oligomerization and thus aborts apoptotic signaling downstream of the TNF family death receptors TNFR1, Fas, and TRAIL... Some pathogens actively promote host apoptosis, while others inhibit Fas-FasL signaling... As the role of apoptosis in modulating host defenses becomes more clear, it will be important to validate the use of cell death manipulators as therapeutics for each infection model, since apoptosis may be detrimental to the host under certain circumstances, such as during systemic bacterial sepsis... Continued investigation of the mechanisms by which pathogens manipulate apoptosis to alter host responses, via a combination of intracellular or extracellular activities on either effector cells or target cells, will provide insight for the development of future therapeutics.

Show MeSH
Related in: MedlinePlus