Abstract
Meningococcus utilizes β-arrestin selective activation of endothelial cell β2 adrenergic receptor (β2AR) to cause meningitis in humans. Molecular mechanisms of receptor activation by the pathogen and of its species selectivity remained elusive. We report that β2AR activation requires two asparagine-branched glycan chains with terminally exposed N-acetyl-neuraminic acid (sialic acid, Neu5Ac) residues located at a specific distance in its N-terminus, while being independent of surrounding amino-acid residues. Meningococcus triggers receptor signaling by exerting direct and hemodynamic-promoted traction forces on β2AR glycans. Similar activation is recapitulated with beads coated with Neu5Ac-binding lectins, submitted to mechanical stimulation. This previously unknown glycan-dependent mode of allosteric mechanical activation of a G protein-coupled receptor contributes to meningococcal species selectivity, since Neu5Ac is only abundant in humans due to the loss of CMAH, the enzyme converting Neu5Ac into N-glycolyl-neuraminic acid in other mammals. It represents an additional mechanism of evolutionary adaptation of a pathogen to its host.
Highlights
Meningococcus utilizes β-arrestin selective activation of endothelial cell β2 adrenergic receptor (β2AR) to cause meningitis in humans
To further demonstrate that meningococcal pilins PilV and PilE interact with the β2AR N-terminus, we used a homogeneous time-resolved fluorescence energy transfer (HTRF)-based assay in intact cells (Fig. 1a)
Human HEK-293 or baby hamster kidney (BHK) cells were transfected with a construct coding for the HA epitope, followed by the first 27 aminoacid residues of the human β2AR, corresponding to the Nterminal extracellular region (EC1), the first transmembrane domain (TM1), and the first residues of the first intracellular loop, fused in phase upstream of green fluorescent protein (GFP)
Summary
Meningococcus utilizes β-arrestin selective activation of endothelial cell β2 adrenergic receptor (β2AR) to cause meningitis in humans. Similar activation is recapitulated with beads coated with Neu5Ac-binding lectins, submitted to mechanical stimulation This previously unknown glycan-dependent mode of allosteric mechanical activation of a G protein-coupled receptor contributes to meningococcal species selectivity, since Neu5Ac is only abundant in humans due to the loss of CMAH, the enzyme converting Neu5Ac into N-glycolyl-neuraminic acid in other mammals. Tfp are made of the assembly in helical fibers of a core pilin subunit, PilE, and of other less abundant (minor) pilins, such as PilV, PilX, or ComP, which are structurally similar to PilE6,7 They trigger signaling cascades in host cells leading to the stabilization of bacterial colonies at the endothelial cell surface and the subsequent translocation of bacteria through endothelial barriers[8,9,10]. Substituting the N-terminal region of the infection-incompetent angiotensin II receptor AT1R with that of the human β2AR produced a chimeric receptor that could be activated by meningococci in vitro[9], suggesting that some direct or indirect N. meningitidis interaction with the β2AR N-terminus might mediate β-arrestin-selective signaling
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