Bacterial effector binding to ribosomal protein s3 subverts NF-kappaB function.

Enteric bacterial pathogens cause food borne disease, which constitutes an enormous economic and health burden. Enterohemorrhagic Escherichia coli (EHEC) causes a severe bloody diarrhea following transmission to humans through various means, including contaminated beef and vegetable products, water,...

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Autores principales:	Xiaofei Gao, Fengyi Wan, Kristina Mateo, Eduardo Callegari, Dan Wang, Wanyin Deng, Jose Puente, Feng Li, Michael S Chaussee, B Brett Finlay, Michael J Lenardo, Philip R Hardwidge
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/2021e29555c64c169eff002cdcfedc74
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spelling	oai:doaj.org-article:2021e29555c64c169eff002cdcfedc742021-11-25T05:48:24ZBacterial effector binding to ribosomal protein s3 subverts NF-kappaB function.1553-73661553-737410.1371/journal.ppat.1000708https://doaj.org/article/2021e29555c64c169eff002cdcfedc742009-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20041225/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Enteric bacterial pathogens cause food borne disease, which constitutes an enormous economic and health burden. Enterohemorrhagic Escherichia coli (EHEC) causes a severe bloody diarrhea following transmission to humans through various means, including contaminated beef and vegetable products, water, or through contact with animals. EHEC also causes a potentially fatal kidney disease (hemolytic uremic syndrome) for which there is no effective treatment or prophylaxis. EHEC and other enteric pathogens (e.g., enteropathogenic E. coli (EPEC), Salmonella, Shigella, Yersinia) utilize a type III secretion system (T3SS) to inject virulence proteins (effectors) into host cells. While it is known that T3SS effectors subvert host cell function to promote diarrheal disease and bacterial transmission, in many cases, the mechanisms by which these effectors bind to host proteins and disrupt the normal function of intestinal epithelial cells have not been completely characterized. In this study, we present evidence that the E. coli O157:H7 nleH1 and nleH2 genes encode T3SS effectors that bind to the human ribosomal protein S3 (RPS3), a subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) transcriptional complexes. NleH1 and NleH2 co-localized with RPS3 in the cytoplasm, but not in cell nuclei. The N-terminal region of both NleH1 and NleH2 was required for binding to the N-terminus of RPS3. NleH1 and NleH2 are autophosphorylated Ser/Thr protein kinases, but their binding to RPS3 is independent of kinase activity. NleH1, but not NleH2, reduced the nuclear abundance of RPS3 without altering the p50 or p65 NF-kappaB subunits or affecting the phosphorylation state or abundance of the inhibitory NF-kappaB chaperone IkappaBalpha NleH1 repressed the transcription of a RPS3/NF-kappaB-dependent reporter plasmid, but did not inhibit the transcription of RPS3-independent reporters. In contrast, NleH2 stimulated RPS3-dependent transcription, as well as an AP-1-dependent reporter. We identified a region of NleH1 (N40-K45) that is at least partially responsible for the inhibitory activity of NleH1 toward RPS3. Deleting nleH1 from E. coli O157:H7 produced a hypervirulent phenotype in a gnotobiotic piglet model of Shiga toxin-producing E. coli infection. We suggest that NleH may disrupt host innate immune responses by binding to a cofactor of host transcriptional complexes.Xiaofei GaoFengyi WanKristina MateoEduardo CallegariDan WangWanyin DengJose PuenteFeng LiMichael S ChausseeB Brett FinlayMichael J LenardoPhilip R HardwidgePublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 5, Iss 12, p e1000708 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Xiaofei Gao Fengyi Wan Kristina Mateo Eduardo Callegari Dan Wang Wanyin Deng Jose Puente Feng Li Michael S Chaussee B Brett Finlay Michael J Lenardo Philip R Hardwidge Bacterial effector binding to ribosomal protein s3 subverts NF-kappaB function.
description	Enteric bacterial pathogens cause food borne disease, which constitutes an enormous economic and health burden. Enterohemorrhagic Escherichia coli (EHEC) causes a severe bloody diarrhea following transmission to humans through various means, including contaminated beef and vegetable products, water, or through contact with animals. EHEC also causes a potentially fatal kidney disease (hemolytic uremic syndrome) for which there is no effective treatment or prophylaxis. EHEC and other enteric pathogens (e.g., enteropathogenic E. coli (EPEC), Salmonella, Shigella, Yersinia) utilize a type III secretion system (T3SS) to inject virulence proteins (effectors) into host cells. While it is known that T3SS effectors subvert host cell function to promote diarrheal disease and bacterial transmission, in many cases, the mechanisms by which these effectors bind to host proteins and disrupt the normal function of intestinal epithelial cells have not been completely characterized. In this study, we present evidence that the E. coli O157:H7 nleH1 and nleH2 genes encode T3SS effectors that bind to the human ribosomal protein S3 (RPS3), a subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) transcriptional complexes. NleH1 and NleH2 co-localized with RPS3 in the cytoplasm, but not in cell nuclei. The N-terminal region of both NleH1 and NleH2 was required for binding to the N-terminus of RPS3. NleH1 and NleH2 are autophosphorylated Ser/Thr protein kinases, but their binding to RPS3 is independent of kinase activity. NleH1, but not NleH2, reduced the nuclear abundance of RPS3 without altering the p50 or p65 NF-kappaB subunits or affecting the phosphorylation state or abundance of the inhibitory NF-kappaB chaperone IkappaBalpha NleH1 repressed the transcription of a RPS3/NF-kappaB-dependent reporter plasmid, but did not inhibit the transcription of RPS3-independent reporters. In contrast, NleH2 stimulated RPS3-dependent transcription, as well as an AP-1-dependent reporter. We identified a region of NleH1 (N40-K45) that is at least partially responsible for the inhibitory activity of NleH1 toward RPS3. Deleting nleH1 from E. coli O157:H7 produced a hypervirulent phenotype in a gnotobiotic piglet model of Shiga toxin-producing E. coli infection. We suggest that NleH may disrupt host innate immune responses by binding to a cofactor of host transcriptional complexes.
format	article
author	Xiaofei Gao Fengyi Wan Kristina Mateo Eduardo Callegari Dan Wang Wanyin Deng Jose Puente Feng Li Michael S Chaussee B Brett Finlay Michael J Lenardo Philip R Hardwidge
author_facet	Xiaofei Gao Fengyi Wan Kristina Mateo Eduardo Callegari Dan Wang Wanyin Deng Jose Puente Feng Li Michael S Chaussee B Brett Finlay Michael J Lenardo Philip R Hardwidge
author_sort	Xiaofei Gao
title	Bacterial effector binding to ribosomal protein s3 subverts NF-kappaB function.
title_short	Bacterial effector binding to ribosomal protein s3 subverts NF-kappaB function.
title_full	Bacterial effector binding to ribosomal protein s3 subverts NF-kappaB function.
title_fullStr	Bacterial effector binding to ribosomal protein s3 subverts NF-kappaB function.
title_full_unstemmed	Bacterial effector binding to ribosomal protein s3 subverts NF-kappaB function.
title_sort	bacterial effector binding to ribosomal protein s3 subverts nf-kappab function.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/2021e29555c64c169eff002cdcfedc74
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Bacterial effector binding to ribosomal protein s3 subverts NF-kappaB function.

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