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Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif)

Cycle inhibiting factors (Cifs) are virulence proteins secreted by the type III secretion system of some Gram-negative pathogenic bacteria including Burkholderia pseudomallei. Cif is known to function to deamidate Nedd8, leading to inhibition of Cullin E3 ubiquitin ligases (CRL) and consequently ind...

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Autores principales: Ng, Mei Ying, Wang, Mei, Casey, Patrick J., Gan, Yunn-Hwen, Hagen, Thilo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293191/
https://www.ncbi.nlm.nih.gov/pubmed/28166272
http://dx.doi.org/10.1371/journal.pone.0171464
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author Ng, Mei Ying
Wang, Mei
Casey, Patrick J.
Gan, Yunn-Hwen
Hagen, Thilo
author_facet Ng, Mei Ying
Wang, Mei
Casey, Patrick J.
Gan, Yunn-Hwen
Hagen, Thilo
author_sort Ng, Mei Ying
collection PubMed
description Cycle inhibiting factors (Cifs) are virulence proteins secreted by the type III secretion system of some Gram-negative pathogenic bacteria including Burkholderia pseudomallei. Cif is known to function to deamidate Nedd8, leading to inhibition of Cullin E3 ubiquitin ligases (CRL) and consequently induction of cell cycle arrest. Here we show that Cif can function as a potent activator of MAPK/ERK signaling without significant activation of other signaling pathways downstream of receptor tyrosine kinases. Importantly, we found that the ability of Cif to activate ERK is dependent on its deamidase activity, but independent of Cullin E3 ligase inhibition. This suggests that apart from Nedd8, other cellular targets of Cif-dependent deamidation exist. We provide evidence that the mechanism involved in Cif-mediated ERK activation is dependent on recruitment of the Grb2-SOS1 complex to the plasma membrane. Further investigation revealed that Cif appears to modify the phosphorylation status of SOS1 in a region containing the CDC25-H and proline-rich domains. It is known that prolonged Cullin E3 ligase inhibition leads to cellular apoptosis. Therefore, we hypothesize that ERK activation is an important mechanism to counter the pro-apoptotic effects of Cif. Indeed, we show that Cif dependent ERK activation promotes phosphorylation of the proapoptotic protein Bim, thereby potentially conferring a pro-survival signal. In summary, we identified a novel deamidation-dependent mechanism of action of the B. pseudomallei virulence factor Cif/CHBP to activate MAPK/ERK signaling. Our study demonstrates that bacterial proteins such as Cif can serve as useful molecular tools to uncover novel aspects of mammalian signaling pathways.
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spelling pubmed-52931912017-02-17 Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif) Ng, Mei Ying Wang, Mei Casey, Patrick J. Gan, Yunn-Hwen Hagen, Thilo PLoS One Research Article Cycle inhibiting factors (Cifs) are virulence proteins secreted by the type III secretion system of some Gram-negative pathogenic bacteria including Burkholderia pseudomallei. Cif is known to function to deamidate Nedd8, leading to inhibition of Cullin E3 ubiquitin ligases (CRL) and consequently induction of cell cycle arrest. Here we show that Cif can function as a potent activator of MAPK/ERK signaling without significant activation of other signaling pathways downstream of receptor tyrosine kinases. Importantly, we found that the ability of Cif to activate ERK is dependent on its deamidase activity, but independent of Cullin E3 ligase inhibition. This suggests that apart from Nedd8, other cellular targets of Cif-dependent deamidation exist. We provide evidence that the mechanism involved in Cif-mediated ERK activation is dependent on recruitment of the Grb2-SOS1 complex to the plasma membrane. Further investigation revealed that Cif appears to modify the phosphorylation status of SOS1 in a region containing the CDC25-H and proline-rich domains. It is known that prolonged Cullin E3 ligase inhibition leads to cellular apoptosis. Therefore, we hypothesize that ERK activation is an important mechanism to counter the pro-apoptotic effects of Cif. Indeed, we show that Cif dependent ERK activation promotes phosphorylation of the proapoptotic protein Bim, thereby potentially conferring a pro-survival signal. In summary, we identified a novel deamidation-dependent mechanism of action of the B. pseudomallei virulence factor Cif/CHBP to activate MAPK/ERK signaling. Our study demonstrates that bacterial proteins such as Cif can serve as useful molecular tools to uncover novel aspects of mammalian signaling pathways. Public Library of Science 2017-02-06 /pmc/articles/PMC5293191/ /pubmed/28166272 http://dx.doi.org/10.1371/journal.pone.0171464 Text en © 2017 Ng et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ng, Mei Ying
Wang, Mei
Casey, Patrick J.
Gan, Yunn-Hwen
Hagen, Thilo
Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif)
title Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif)
title_full Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif)
title_fullStr Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif)
title_full_unstemmed Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif)
title_short Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif)
title_sort activation of mapk/erk signaling by burkholderia pseudomallei cycle inhibiting factor (cif)
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293191/
https://www.ncbi.nlm.nih.gov/pubmed/28166272
http://dx.doi.org/10.1371/journal.pone.0171464
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