<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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2020-10-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01733-20 |
| _version_ | 1818825909631713280 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T00:19:16Z |
| format | Article |
| id | doaj.art-cfc9f1099b3449c086b2907f5e856696 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-19T00:19:16Z |
| publishDate | 2020-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-cfc9f1099b3449c086b2907f5e8566962022-12-21T20:45:37ZengAmerican Society for MicrobiologymBio2150-75112020-10-0111510.1128/mBio.01733-20<named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Reduces SUMOylation To Limit Host Defense ResponsesJoana Sá-Pessoa0Kornelia Przybyszewska1Filipe Nuno Vasconcelos2Amy Dumigan3Christian G. Frank4Laura Hobley5Jose A. Bengoechea6Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United KingdomWellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United KingdomWellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United KingdomWellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United KingdomWellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United KingdomWellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United KingdomWellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United KingdomABSTRACT 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.https://journals.asm.org/doi/10.1128/mBio.01733-20Klebsiella pneumoniaeSUMOylationlet-7SENP2interferonNEDDylation |
| spellingShingle | 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 mBio Klebsiella pneumoniae SUMOylation let-7 SENP2 interferon NEDDylation |
| title | <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_short | <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 |
| topic | Klebsiella pneumoniae SUMOylation let-7 SENP2 interferon NEDDylation |
| url | https://journals.asm.org/doi/10.1128/mBio.01733-20 |
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