Master Sculptor at Work: Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Infection Uniquely Modifies Mitochondrial Proteolysis during Its Control of Human Cell Death

ABSTRACT Enteropathogenic Escherichia coli (EPEC) causes severe diarrheal disease and is present globally. EPEC virulence requires a bacterial type III secretion system to inject >20 effector proteins into human intestinal cells. Three effectors travel to mitochondria and modulate apoptosis; howe...

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Autores principales:	Natalie C. Marshall, Maichael Thejoe, Theo Klein, Antonio Serapio-Palacios, Andrew S. Santos, Niklas von Krosigk, Jayachandran N. Kizhakkedathu, Nikolay Stoynov, Leonard J. Foster, Christopher M. Overall, B. Brett Finlay
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	infection mitochondria EPEC type III secretion system apoptosis proteomics Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1168c70f08f34f7f86a42c6a0f86970c
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spelling	oai:doaj.org-article:1168c70f08f34f7f86a42c6a0f86970c2021-12-02T19:47:39ZMaster Sculptor at Work: Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Infection Uniquely Modifies Mitochondrial Proteolysis during Its Control of Human Cell Death10.1128/mSystems.00283-202379-5077https://doaj.org/article/1168c70f08f34f7f86a42c6a0f86970c2020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00283-20https://doaj.org/toc/2379-5077ABSTRACT Enteropathogenic Escherichia coli (EPEC) causes severe diarrheal disease and is present globally. EPEC virulence requires a bacterial type III secretion system to inject >20 effector proteins into human intestinal cells. Three effectors travel to mitochondria and modulate apoptosis; however, the mechanisms by which effectors control apoptosis from within mitochondria are unknown. To identify and quantify global changes in mitochondrial proteolysis during infection, we applied the mitochondrial terminal proteomics technique mitochondrial stable isotope labeling by amino acids in cell culture-terminal amine isotopic labeling of substrates (MS-TAILS). MS-TAILS identified 1,695 amino N-terminal peptides from 1,060 unique proteins and 390 N-terminal peptides from 215 mitochondrial proteins at a false discovery rate of 0.01. Infection modified 230 cellular and 40 mitochondrial proteins, generating 27 cleaved mitochondrial neo-N termini, demonstrating altered proteolytic processing within mitochondria. To distinguish proteolytic events specific to EPEC from those of canonical apoptosis, we compared mitochondrial changes during infection with those reported from chemically induced apoptosis. During infection, fewer than half of all mitochondrial cleavages were previously described for canonical apoptosis, and we identified nine mitochondrial proteolytic sites not previously reported, including several in proteins with an annotated role in apoptosis, although none occurred at canonical Asp-Glu-Val-Asp (DEVD) sites associated with caspase cleavage. The identification and quantification of novel neo-N termini evidences the involvement of noncaspase human or EPEC protease(s) resulting from mitochondrial-targeting effectors that modulate cell death upon infection. All proteomics data are available via ProteomeXchange with identifier PXD016994. IMPORTANCE To our knowledge, this is the first study of the mitochondrial proteome or N-terminome during bacterial infection. Identified cleavage sites that had not been previously reported in the mitochondrial N-terminome and that were not generated in canonical apoptosis revealed a pathogen-specific strategy to control human cell apoptosis. These data inform new mechanisms of virulence factors targeting mitochondria and apoptosis during infection and highlight how enteropathogenic Escherichia coli (EPEC) manipulates human cell death pathways during infection, including candidate substrates of an EPEC protease within mitochondria. This understanding informs the development of new antivirulence strategies against the many human pathogens that target mitochondria during infection. Therefore, mitochondrial stable isotope labeling by amino acids in cell culture-terminal amine isotopic labeling of substrates (MS-TAILS) is useful for studying other pathogens targeting human cell compartments.Natalie C. MarshallMaichael ThejoeTheo KleinAntonio Serapio-PalaciosAndrew S. SantosNiklas von KrosigkJayachandran N. KizhakkedathuNikolay StoynovLeonard J. FosterChristopher M. OverallB. Brett FinlayAmerican Society for MicrobiologyarticleinfectionmitochondriaEPECtype III secretion systemapoptosisproteomicsMicrobiologyQR1-502ENmSystems, Vol 5, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	infection mitochondria EPEC type III secretion system apoptosis proteomics Microbiology QR1-502
spellingShingle	infection mitochondria EPEC type III secretion system apoptosis proteomics Microbiology QR1-502 Natalie C. Marshall Maichael Thejoe Theo Klein Antonio Serapio-Palacios Andrew S. Santos Niklas von Krosigk Jayachandran N. Kizhakkedathu Nikolay Stoynov Leonard J. Foster Christopher M. Overall B. Brett Finlay Master Sculptor at Work: Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Infection Uniquely Modifies Mitochondrial Proteolysis during Its Control of Human Cell Death
description	ABSTRACT Enteropathogenic Escherichia coli (EPEC) causes severe diarrheal disease and is present globally. EPEC virulence requires a bacterial type III secretion system to inject >20 effector proteins into human intestinal cells. Three effectors travel to mitochondria and modulate apoptosis; however, the mechanisms by which effectors control apoptosis from within mitochondria are unknown. To identify and quantify global changes in mitochondrial proteolysis during infection, we applied the mitochondrial terminal proteomics technique mitochondrial stable isotope labeling by amino acids in cell culture-terminal amine isotopic labeling of substrates (MS-TAILS). MS-TAILS identified 1,695 amino N-terminal peptides from 1,060 unique proteins and 390 N-terminal peptides from 215 mitochondrial proteins at a false discovery rate of 0.01. Infection modified 230 cellular and 40 mitochondrial proteins, generating 27 cleaved mitochondrial neo-N termini, demonstrating altered proteolytic processing within mitochondria. To distinguish proteolytic events specific to EPEC from those of canonical apoptosis, we compared mitochondrial changes during infection with those reported from chemically induced apoptosis. During infection, fewer than half of all mitochondrial cleavages were previously described for canonical apoptosis, and we identified nine mitochondrial proteolytic sites not previously reported, including several in proteins with an annotated role in apoptosis, although none occurred at canonical Asp-Glu-Val-Asp (DEVD) sites associated with caspase cleavage. The identification and quantification of novel neo-N termini evidences the involvement of noncaspase human or EPEC protease(s) resulting from mitochondrial-targeting effectors that modulate cell death upon infection. All proteomics data are available via ProteomeXchange with identifier PXD016994. IMPORTANCE To our knowledge, this is the first study of the mitochondrial proteome or N-terminome during bacterial infection. Identified cleavage sites that had not been previously reported in the mitochondrial N-terminome and that were not generated in canonical apoptosis revealed a pathogen-specific strategy to control human cell apoptosis. These data inform new mechanisms of virulence factors targeting mitochondria and apoptosis during infection and highlight how enteropathogenic Escherichia coli (EPEC) manipulates human cell death pathways during infection, including candidate substrates of an EPEC protease within mitochondria. This understanding informs the development of new antivirulence strategies against the many human pathogens that target mitochondria during infection. Therefore, mitochondrial stable isotope labeling by amino acids in cell culture-terminal amine isotopic labeling of substrates (MS-TAILS) is useful for studying other pathogens targeting human cell compartments.
format	article
author	Natalie C. Marshall Maichael Thejoe Theo Klein Antonio Serapio-Palacios Andrew S. Santos Niklas von Krosigk Jayachandran N. Kizhakkedathu Nikolay Stoynov Leonard J. Foster Christopher M. Overall B. Brett Finlay
author_facet	Natalie C. Marshall Maichael Thejoe Theo Klein Antonio Serapio-Palacios Andrew S. Santos Niklas von Krosigk Jayachandran N. Kizhakkedathu Nikolay Stoynov Leonard J. Foster Christopher M. Overall B. Brett Finlay
author_sort	Natalie C. Marshall
title	Master Sculptor at Work: Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Infection Uniquely Modifies Mitochondrial Proteolysis during Its Control of Human Cell Death
title_short	Master Sculptor at Work: Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Infection Uniquely Modifies Mitochondrial Proteolysis during Its Control of Human Cell Death
title_full	Master Sculptor at Work: Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Infection Uniquely Modifies Mitochondrial Proteolysis during Its Control of Human Cell Death
title_fullStr	Master Sculptor at Work: Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Infection Uniquely Modifies Mitochondrial Proteolysis during Its Control of Human Cell Death
title_full_unstemmed	Master Sculptor at Work: Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Infection Uniquely Modifies Mitochondrial Proteolysis during Its Control of Human Cell Death
title_sort	master sculptor at work: enteropathogenic <named-content content-type="genus-species">escherichia coli</named-content> infection uniquely modifies mitochondrial proteolysis during its control of human cell death
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/1168c70f08f34f7f86a42c6a0f86970c
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Master Sculptor at Work: Enteropathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Infection Uniquely Modifies Mitochondrial Proteolysis during Its Control of Human Cell Death

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