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. and Churchward, C.P. and Karlyshev, A.V. and Eleftheriadou, O. and Snabaitis, A.K. and Longman, M.R. and 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 (14). pp. 2247-2260. ISSN 1476-5381

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Abstract

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.

EXPERIMENTAL APPROACH

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.

KEY RESULTS

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.

Item Type: Article
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.wiley.com/doi/10.1111/bph.13660/abstract;jsessionid=7A4B021B990FB7148D110188453DAA34.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/
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences > School of Molecular Medical Sciences > Bacteriology
Identification Number: 10.1111/bph.13660
Depositing User: Griffin, Ruth
Date Deposited: 13 Dec 2017 08:37
Last Modified: 17 Apr 2018 14:53
URI: http://eprints.nottingham.ac.uk/id/eprint/48687

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