R.A.G. da Silva email@example.com
The role of apolipoprotein N-acyl transferase, Lnt, in the lipidation of factor H binding protein of Neisseria meningitidis strain MC58 and its potential as a drug target
da Silva, R.A.G.; Churchward, C.P.; Karlyshev, A.V.; Eleftheriadou, O.; Snabaitis, A.K.; Longman, M.R.; Ryan, A.; Griffin, Ruth
C.P. Churchward firstname.lastname@example.org
A.V. Karlyshev email@example.com
O. Eleftheriadou firstname.lastname@example.org
A.K. Snabaitis email@example.com
M.R. Longman firstname.lastname@example.org
A. Ryan email@example.com
Ruth Griffin firstname.lastname@example.org
BACKGROUND AND PURPOSE
The level of cell surface expression of the meningococcal vaccine antigen, Factor H binding protein (FHbp) varies between and within strains and this limits the breadth of strains that can be targeted by FHbp-based vaccines. The molecular pathway controlling expression of FHbp at the cell surface, including its lipidation, sorting to the outer membrane and export, and the potential regulation of this pathway have not been investigated until now. This knowledge will aid our evaluation of FHbp vaccines.
A meningococcal transposon library was screened by whole cell immuno-dot blotting using an anti-FHbp antibody to identify a mutant with reduced binding and the disrupted gene was determined.
In a mutant with markedly reduced binding, the transposon was located in the lnt gene which encodes apolipoprotein N-acyl transferase, Lnt, responsible for the addition of the third fatty acid to apolipoproteins prior to their sorting to the outer membrane. We provide data indicating that in the Lnt mutant, FHbp is diacylated and its expression within the cell is reduced 10 fold, partly due to inhibition of transcription. Furthermore the Lnt mutant showed 64 fold and 16 fold increase in susceptibility to rifampicin and ciprofloxacin respectively.
CONCLUSION AND IMPLICATIONS
We speculate that the inefficient sorting of diacylated FHbp in the meningococcus results in its accumulation in the periplasm inducing an envelope stress response to down-regulate its expression. We propose Lnt as a potential novel drug target for combination therapy with antibiotics.
|Journal Article Type||Article|
|Publication Date||Jun 23, 2017|
|Journal||British Journal of Pharmacology|
|Peer Reviewed||Peer Reviewed|
|APA6 Citation||da Silva, R., Churchward, C., Karlyshev, A., Eleftheriadou, O., Snabaitis, A., Longman, M., …Griffin, R. (2017). The role of apolipoprotein N-acyl transferase, Lnt, in the lipidation of factor H binding protein of Neisseria meningitidis strain MC58 and its potential as a drug target. British Journal of Pharmacology, 174(14), https://doi.org/10.1111/bph.13660|
|Copyright Statement||Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf|
|Additional Information||This is the peer reviewed version of the following article: da Silva, R. A. G., Churchward, C. P., Karlyshev, A. V., Eleftheriadou, O., Snabaitis, A. K., Longman, M. R., Ryan, A., and Griffin, R. (2017) The role of apolipoprotein N-acyl transferase, Lnt, in the lipidation of factor H binding protein of Neisseria meningitidis strain MC58 and its potential as a drug target. British Journal of Pharmacology, 174: 2247–2260. doi: 10.1111/bph.13660., which has been published in final form at http://onlinelibrary.wi...D110188453DAA34.f04t02. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. The REF eligible version of this article can be found in the Kingston University repository at http://eprints.kingston.ac.uk/36421/|
Accepted article BJP 2017.pdf
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf
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