Sialic acid mediated mechanical activation of β2 adrenergic receptors by bacterial pili

Zoe Virion1, Stéphane Doly2, Kusumika Saha2

  • 1Inserm, U1151, CNRS UMR 8253, Institut-Necker-Enfants-Malades, Université de Paris, Paris, France.

Nature Communications
|October 20, 2019
PubMed

Insights

Meningococcus bacteria activate human β2 adrenergic receptors (β2AR) through mechanical forces on its sugar chains, not amino acids. This glycan-dependent activation explains pathogen species selectivity in humans.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Biochemistry

Background:

  • Neisseria meningitidis (meningococcus) causes meningitis by activating human endothelial cell β2 adrenergic receptors (β2AR).
  • The precise molecular mechanisms of this pathogen-induced receptor activation and its species selectivity were previously unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which meningococcus activates β2AR.
  • To understand the basis of meningococcal species selectivity in host infection.

Main Methods:

  • Investigated the role of N-terminal glycan chains and mechanical forces in β2AR activation by meningococcus.
  • Utilized beads coated with N-acetyl-neuraminic acid (Neu5Ac)-binding lectins to mimic pathogen-induced mechanical stimulation.

Main Results:

  • β2AR activation by meningococcus depends on two specific N-terminal glycan chains with terminal N-acetyl-neuraminic acid (Neu5Ac) residues, independent of surrounding amino acids.
  • Meningococcus triggers β2AR signaling via direct and hemodynamic-promoted traction forces on these glycans.
  • Mechanical stimulation of Neu5Ac-coated beads recapitulated this activation mechanism.

Conclusions:

  • Discovered a novel, glycan-dependent, allosteric mechanical mode of G protein-coupled receptor activation.
  • This mechanism explains meningococcal species selectivity, as abundant human Neu5Ac contrasts with its lower levels in other mammals due to CMAH enzyme loss.
  • Identified a new pathway for pathogen adaptation to its host environment.

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