Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0171464
Title: Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif)
Authors: Ng M.Y.
Wang M. 
Casey P.J. 
Gan Y.-H. 
Hagen T. 
Keywords: bacterial protein
BIM protein
cullin
cycle inhibiting factor
growth factor receptor bound protein 2
mitogen activated protein kinase
SOS protein
unclassified drug
bacterial protein
mitogen activated protein kinase
protein tyrosine phosphatase
virulence factor
apoptosis
Article
Burkholderia pseudomallei
cell membrane
controlled study
deamination
embryo
enzyme activation
enzyme inhibition
human
human cell
nonhuman
protein domain
protein phosphorylation
signal transduction
Burkholderia pseudomallei
cell line
chemistry
gene expression
genetics
melioidosis
metabolism
microbiology
pathogenicity
phosphorylation
Bacterial Proteins
Bcl-2-Like Protein 11
Burkholderia pseudomallei
cdc25 Phosphatases
Cell Line
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases
Gene Expression
Humans
MAP Kinase Signaling System
Melioidosis
Phosphorylation
Protein Interaction Domains and Motifs
SOS1 Protein
Virulence Factors
Issue Date: 2017
Publisher: Public Library of Science
Citation: Ng M.Y., Wang M., Casey P.J., Gan Y.-H., Hagen T. (2017). Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif). PLoS ONE 12 (2) : e0171464. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0171464
Abstract: 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 Cifdependent deamidation exist. We provide evidence that the mechanism involved in Cifmediated 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. © 2017 Ng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/166021
ISSN: 19326203
DOI: 10.1371/journal.pone.0171464
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