<named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Reduces SUMOylation To Limit Host Defense Responses

ABSTRACT Klebsiella pneumoniae is an important cause of multidrug-resistant infections worldwide. Understanding the virulence mechanisms of K. pneumoniae is a priority and timely to design new therapeutics. Here, we demonstrate that K. pneumoniae limits the SUMOylation of host proteins in epithelial...

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Autores principales:	Joana Sá-Pessoa, Kornelia Przybyszewska, Filipe Nuno Vasconcelos, Amy Dumigan, Christian G. Frank, Laura Hobley, Jose A. Bengoechea
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Klebsiella pneumoniae SUMOylation let-7 SENP2 interferon NEDDylation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cfc9f1099b3449c086b2907f5e856696
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spelling	oai:doaj.org-article:cfc9f1099b3449c086b2907f5e8566962021-11-15T16:19:08Z<named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Reduces SUMOylation To Limit Host Defense Responses10.1128/mBio.01733-202150-7511https://doaj.org/article/cfc9f1099b3449c086b2907f5e8566962020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01733-20https://doaj.org/toc/2150-7511ABSTRACT Klebsiella pneumoniae is an important cause of multidrug-resistant infections worldwide. Understanding the virulence mechanisms of K. pneumoniae is a priority and timely to design new therapeutics. Here, we demonstrate that K. pneumoniae limits the SUMOylation of host proteins in epithelial cells and macrophages (mouse and human) to subvert cell innate immunity. Mechanistically, in lung epithelial cells, Klebsiella increases the levels of the deSUMOylase SENP2 in the cytosol by affecting its K48 ubiquitylation and its subsequent degradation by the ubiquitin proteasome. This is dependent on Klebsiella preventing the NEDDylation of the Cullin-1 subunit of the ubiquitin ligase complex E3-SCF-βTrCP by exploiting the CSN5 deNEDDylase. Klebsiella induces the expression of CSN5 in an epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-extracellular signal-regulated kinase (ERK)-glycogen synthase kinase 3 beta (GSK3β) signaling pathway-dependent manner. In macrophages, Toll-like receptor 4 (TLR4)-TRAM-TRIF-induced type I interferon (IFN) via IFN receptor 1 (IFNAR1)-controlled signaling mediates Klebsiella-triggered decrease in the levels of SUMOylation via let-7 microRNAs (miRNAs). Our results revealed the crucial role played by Klebsiella polysaccharides, the capsule, and the lipopolysaccharide (LPS) O-polysaccharide, to decrease the levels of SUMO-conjugated proteins in epithelial cells and macrophages. A Klebsiella-induced decrease in SUMOylation promotes infection by limiting the activation of inflammatory responses and increasing intracellular survival in macrophages. IMPORTANCE Klebsiella pneumoniae has been singled out as an urgent threat to human health due to the increasing isolation of strains resistant to “last-line” antimicrobials, narrowing the treatment options against Klebsiella infections. Unfortunately, at present, we cannot identify candidate compounds in late-stage development for treatment of multidrug-resistant Klebsiella infections; this pathogen is exemplary of the mismatch between unmet medical needs and the current antimicrobial research and development pipeline. Furthermore, there is still limited evidence on K. pneumoniae pathogenesis at the molecular and cellular levels in the context of the interactions between bacterial pathogens and their hosts. In this research, we have uncovered a sophisticated strategy employed by Klebsiella to subvert the activation of immune defenses by controlling the modification of proteins. Our research may open opportunities to develop new therapeutics based on counteracting this Klebsiella-controlled immune evasion strategy.Joana Sá-PessoaKornelia PrzybyszewskaFilipe Nuno VasconcelosAmy DumiganChristian G. FrankLaura HobleyJose A. BengoecheaAmerican Society for MicrobiologyarticleKlebsiella pneumoniaeSUMOylationlet-7SENP2interferonNEDDylationMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Klebsiella pneumoniae SUMOylation let-7 SENP2 interferon NEDDylation Microbiology QR1-502
spellingShingle	Klebsiella pneumoniae SUMOylation let-7 SENP2 interferon NEDDylation Microbiology QR1-502 Joana Sá-Pessoa Kornelia Przybyszewska Filipe Nuno Vasconcelos Amy Dumigan Christian G. Frank Laura Hobley Jose A. Bengoechea <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Reduces SUMOylation To Limit Host Defense Responses
description	ABSTRACT Klebsiella pneumoniae is an important cause of multidrug-resistant infections worldwide. Understanding the virulence mechanisms of K. pneumoniae is a priority and timely to design new therapeutics. Here, we demonstrate that K. pneumoniae limits the SUMOylation of host proteins in epithelial cells and macrophages (mouse and human) to subvert cell innate immunity. Mechanistically, in lung epithelial cells, Klebsiella increases the levels of the deSUMOylase SENP2 in the cytosol by affecting its K48 ubiquitylation and its subsequent degradation by the ubiquitin proteasome. This is dependent on Klebsiella preventing the NEDDylation of the Cullin-1 subunit of the ubiquitin ligase complex E3-SCF-βTrCP by exploiting the CSN5 deNEDDylase. Klebsiella induces the expression of CSN5 in an epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-extracellular signal-regulated kinase (ERK)-glycogen synthase kinase 3 beta (GSK3β) signaling pathway-dependent manner. In macrophages, Toll-like receptor 4 (TLR4)-TRAM-TRIF-induced type I interferon (IFN) via IFN receptor 1 (IFNAR1)-controlled signaling mediates Klebsiella-triggered decrease in the levels of SUMOylation via let-7 microRNAs (miRNAs). Our results revealed the crucial role played by Klebsiella polysaccharides, the capsule, and the lipopolysaccharide (LPS) O-polysaccharide, to decrease the levels of SUMO-conjugated proteins in epithelial cells and macrophages. A Klebsiella-induced decrease in SUMOylation promotes infection by limiting the activation of inflammatory responses and increasing intracellular survival in macrophages. IMPORTANCE Klebsiella pneumoniae has been singled out as an urgent threat to human health due to the increasing isolation of strains resistant to “last-line” antimicrobials, narrowing the treatment options against Klebsiella infections. Unfortunately, at present, we cannot identify candidate compounds in late-stage development for treatment of multidrug-resistant Klebsiella infections; this pathogen is exemplary of the mismatch between unmet medical needs and the current antimicrobial research and development pipeline. Furthermore, there is still limited evidence on K. pneumoniae pathogenesis at the molecular and cellular levels in the context of the interactions between bacterial pathogens and their hosts. In this research, we have uncovered a sophisticated strategy employed by Klebsiella to subvert the activation of immune defenses by controlling the modification of proteins. Our research may open opportunities to develop new therapeutics based on counteracting this Klebsiella-controlled immune evasion strategy.
format	article
author	Joana Sá-Pessoa Kornelia Przybyszewska Filipe Nuno Vasconcelos Amy Dumigan Christian G. Frank Laura Hobley Jose A. Bengoechea
author_facet	Joana Sá-Pessoa Kornelia Przybyszewska Filipe Nuno Vasconcelos Amy Dumigan Christian G. Frank Laura Hobley Jose A. Bengoechea
author_sort	Joana Sá-Pessoa
title	<named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Reduces SUMOylation To Limit Host Defense Responses
title_short	<named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Reduces SUMOylation To Limit Host Defense Responses
title_full	<named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Reduces SUMOylation To Limit Host Defense Responses
title_fullStr	<named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Reduces SUMOylation To Limit Host Defense Responses
title_full_unstemmed	<named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Reduces SUMOylation To Limit Host Defense Responses
title_sort	<named-content content-type="genus-species">klebsiella pneumoniae</named-content> reduces sumoylation to limit host defense responses
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/cfc9f1099b3449c086b2907f5e856696
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<named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Reduces SUMOylation To Limit Host Defense Responses

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