Strength of Neisseria meningitidis binding to endothelial cells requires highly-ordered CD147/β2-adrenoceptor clusters assembled by alpha-actinin-4

Neisseria meningitidis (meningococcus) is an invasive bacterial pathogen that colonizes human vessels, causing thrombotic lesions and meningitis. Establishment of tight interactions with endothelial cells is crucial for meningococci to resist hemodynamic forces. Two endothelial receptors, CD147 and the β2-adrenergic receptor (β2AR), are sequentially engaged by meningococci to adhere and promote signaling events leading to vascular colonization, but their spatiotemporal coordination is unknown. Here we report that CD147 and β2AR form constitutive hetero-oligomeric complexes. The scaffolding protein alpha-actinin-4 directly binds to the cytosolic tail of CD147 and governs the assembly of CD147/β2AR complexes in highly-ordered clusters at bacterial adhesion sites. This multi-molecular assembly process increases the binding strength of meningococci to endothelial cells under shear stress, and creates molecular platforms for the elongation of membrane protrusions surrounding adherent bacteria. Thus, the specific organization of cellular receptors has major impacts on host-pathogen interaction.

脑膜炎奈瑟菌（Neisseria meningitidis，又称脑膜炎球菌）是一种侵袭性细菌病原体，可定植于人体血管，引发血栓性损伤与脑膜炎。与内皮细胞建立紧密相互作用，是脑膜炎球菌抵抗血流动力的关键环节。两种内皮受体——CD147与β2肾上腺素能受体（β2-adrenergic receptor, β2AR），会被脑膜炎球菌依次结合以介导黏附，并触发促进血管定植的信号级联反应，但其时空协同机制尚未明确。本研究报道，CD147与β2AR可形成组成型异源寡聚复合物。支架蛋白α-辅肌动蛋白-4（alpha-actinin-4）可直接结合CD147的胞质尾区，并调控CD147/β2AR复合物在细菌黏附位点组装为高度有序的簇状结构。这一多分子组装过程可提升剪切应力下脑膜炎球菌与内皮细胞的结合强度，并为黏附细菌周围的膜突起延伸提供分子平台。由此可见，细胞受体的特定组织形式对宿主-病原体互作具有重要影响。