EspC, an Autotransporter Protein Secreted by Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>, Causes Apoptosis and Necrosis through Caspase and Calpain Activation, Including Direct Procaspase-3 Cleavage

ABSTRACT Enteropathogenic Escherichia coli (EPEC) has the ability to antagonize host apoptosis during infection through promotion and inhibition of effectors injected by the type III secretion system (T3SS), but the total number of these effectors and the overall functional relationships between the...

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Autores principales:	Antonio Serapio-Palacios, Fernando Navarro-Garcia
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1260fe0793124531841de7e80bb0fade
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spelling	oai:doaj.org-article:1260fe0793124531841de7e80bb0fade2021-11-15T15:50:16ZEspC, an Autotransporter Protein Secreted by Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>, Causes Apoptosis and Necrosis through Caspase and Calpain Activation, Including Direct Procaspase-3 Cleavage10.1128/mBio.00479-162150-7511https://doaj.org/article/1260fe0793124531841de7e80bb0fade2016-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00479-16https://doaj.org/toc/2150-7511ABSTRACT Enteropathogenic Escherichia coli (EPEC) has the ability to antagonize host apoptosis during infection through promotion and inhibition of effectors injected by the type III secretion system (T3SS), but the total number of these effectors and the overall functional relationships between these effectors during infection are poorly understood. EspC produced by EPEC cleaves fodrin, paxillin, and focal adhesion kinase (FAK), which are also cleaved by caspases and calpains during apoptosis. Here we show the role of EspC in cell death induced by EPEC. EspC is involved in EPEC-mediated cell death and induces both apoptosis and necrosis in epithelial cells. EspC induces apoptosis through the mitochondrial apoptotic pathway by provoking (i) a decrease in the expression levels of antiapoptotic protein Bcl-2, (ii) translocation of the proapoptotic protein Bax from cytosol to mitochondria, (iii) cytochrome c release from mitochondria to the cytoplasm, (iv) loss of mitochondrial membrane potential, (v) caspase-9 activation, (vi) cleavage of procaspase-3 and (vii) an increase in caspase-3 activity, (viii) PARP proteolysis, and (ix) nuclear fragmentation and an increase in the sub-G1 population. Interestingly, EspC-induced apoptosis was triggered through a dual mechanism involving both independent and dependent functions of its EspC serine protease motif, the direct cleavage of procaspase-3 being dependent on this motif. This is the first report showing a shortcut for induction of apoptosis by the catalytic activity of an EPEC protein. Furthermore, this atypical intrinsic apoptosis appeared to induce necrosis through the activation of calpain and through the increase of intracellular calcium induced by EspC. Our data indicate that EspC plays a relevant role in cell death induced by EPEC. IMPORTANCE EspC, an autotransporter protein with serine protease activity, has cytotoxic effects on epithelial cells during EPEC infection. EspC causes cytotoxicity by cleaving fodrin, a cytoskeletal actin-associated protein, and focal adhesion proteins (i.e., FAK); interestingly, these proteins are also cleaved during apoptosis and necrosis. Here we show that EspC is able to cause cell death, which is characterized by apoptosis: by dissecting the apoptotic pathway and considering that EspC is translocated by an injectisome, we found that EspC induces the mitochondrial apoptotic pathway. Remarkably, EspC activates this pathway by two distinct mechanisms—either by using or not using its serine protease motif. Thus, we show for the first time that this serine protease motif is able to cleave procaspase-3, thereby reaching the terminal stages of caspase cascade activation leading to apoptosis. Furthermore, this overlapped apoptosis appears to potentiate cell death through necrosis, where EspC induces calpain activation and increases intracellular calcium.Antonio Serapio-PalaciosFernando Navarro-GarciaAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 3 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Antonio Serapio-Palacios Fernando Navarro-Garcia EspC, an Autotransporter Protein Secreted by Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>, Causes Apoptosis and Necrosis through Caspase and Calpain Activation, Including Direct Procaspase-3 Cleavage
description	ABSTRACT Enteropathogenic Escherichia coli (EPEC) has the ability to antagonize host apoptosis during infection through promotion and inhibition of effectors injected by the type III secretion system (T3SS), but the total number of these effectors and the overall functional relationships between these effectors during infection are poorly understood. EspC produced by EPEC cleaves fodrin, paxillin, and focal adhesion kinase (FAK), which are also cleaved by caspases and calpains during apoptosis. Here we show the role of EspC in cell death induced by EPEC. EspC is involved in EPEC-mediated cell death and induces both apoptosis and necrosis in epithelial cells. EspC induces apoptosis through the mitochondrial apoptotic pathway by provoking (i) a decrease in the expression levels of antiapoptotic protein Bcl-2, (ii) translocation of the proapoptotic protein Bax from cytosol to mitochondria, (iii) cytochrome c release from mitochondria to the cytoplasm, (iv) loss of mitochondrial membrane potential, (v) caspase-9 activation, (vi) cleavage of procaspase-3 and (vii) an increase in caspase-3 activity, (viii) PARP proteolysis, and (ix) nuclear fragmentation and an increase in the sub-G1 population. Interestingly, EspC-induced apoptosis was triggered through a dual mechanism involving both independent and dependent functions of its EspC serine protease motif, the direct cleavage of procaspase-3 being dependent on this motif. This is the first report showing a shortcut for induction of apoptosis by the catalytic activity of an EPEC protein. Furthermore, this atypical intrinsic apoptosis appeared to induce necrosis through the activation of calpain and through the increase of intracellular calcium induced by EspC. Our data indicate that EspC plays a relevant role in cell death induced by EPEC. IMPORTANCE EspC, an autotransporter protein with serine protease activity, has cytotoxic effects on epithelial cells during EPEC infection. EspC causes cytotoxicity by cleaving fodrin, a cytoskeletal actin-associated protein, and focal adhesion proteins (i.e., FAK); interestingly, these proteins are also cleaved during apoptosis and necrosis. Here we show that EspC is able to cause cell death, which is characterized by apoptosis: by dissecting the apoptotic pathway and considering that EspC is translocated by an injectisome, we found that EspC induces the mitochondrial apoptotic pathway. Remarkably, EspC activates this pathway by two distinct mechanisms—either by using or not using its serine protease motif. Thus, we show for the first time that this serine protease motif is able to cleave procaspase-3, thereby reaching the terminal stages of caspase cascade activation leading to apoptosis. Furthermore, this overlapped apoptosis appears to potentiate cell death through necrosis, where EspC induces calpain activation and increases intracellular calcium.
format	article
author	Antonio Serapio-Palacios Fernando Navarro-Garcia
author_facet	Antonio Serapio-Palacios Fernando Navarro-Garcia
author_sort	Antonio Serapio-Palacios
title	EspC, an Autotransporter Protein Secreted by Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>, Causes Apoptosis and Necrosis through Caspase and Calpain Activation, Including Direct Procaspase-3 Cleavage
title_short	EspC, an Autotransporter Protein Secreted by Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>, Causes Apoptosis and Necrosis through Caspase and Calpain Activation, Including Direct Procaspase-3 Cleavage
title_full	EspC, an Autotransporter Protein Secreted by Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>, Causes Apoptosis and Necrosis through Caspase and Calpain Activation, Including Direct Procaspase-3 Cleavage
title_fullStr	EspC, an Autotransporter Protein Secreted by Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>, Causes Apoptosis and Necrosis through Caspase and Calpain Activation, Including Direct Procaspase-3 Cleavage
title_full_unstemmed	EspC, an Autotransporter Protein Secreted by Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>, Causes Apoptosis and Necrosis through Caspase and Calpain Activation, Including Direct Procaspase-3 Cleavage
title_sort	espc, an autotransporter protein secreted by enteropathogenic <named-content content-type="genus-species">escherichia coli</named-content>, causes apoptosis and necrosis through caspase and calpain activation, including direct procaspase-3 cleavage
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/1260fe0793124531841de7e80bb0fade
work_keys_str_mv	AT antonioserapiopalacios espcanautotransporterproteinsecretedbyenteropathogenicnamedcontentcontenttypegenusspeciesescherichiacolinamedcontentcausesapoptosisandnecrosisthroughcaspaseandcalpainactivationincludingdirectprocaspase3cleavage AT fernandonavarrogarcia espcanautotransporterproteinsecretedbyenteropathogenicnamedcontentcontenttypegenusspeciesescherichiacolinamedcontentcausesapoptosisandnecrosisthroughcaspaseandcalpainactivationincludingdirectprocaspase3cleavage
_version_	1718427443095666688

EspC, an Autotransporter Protein Secreted by Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>, Causes Apoptosis and Necrosis through Caspase and Calpain Activation, Including Direct Procaspase-3 Cleavage

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