Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA.
Integral Molecular, Philadelphia, PA, USA.
Nat Commun. 2024 Oct 26;15(1):9250. doi: 10.1038/s41467-024-53443-7.
The intracellular bacterial pathogen Chlamydia trachomatis replicates within a membrane-bound compartment called the inclusion. Upon infection with several chlamydiae, each bacterium creates its own inclusion, resulting in multiple inclusions within each host cell. Ultimately, these inclusions fuse together in a process that requires the chlamydial protein IncA. Here, we show that inclusions form unique contact sites (inclusion contact sites, ICSs) prior to fusion, that serve as fusogenic platforms in which specific lipids and chlamydial proteins concentrate. Fusion depends on IncA clustering within ICSs and is regulated by PI(3,4)P and sphingolipids. As IncA concentrates within ICSs, its C-terminus likely interacts in trans with IncA on the apposing membrane, securing a high concentration of IncA at fusion sites. This regulatory mechanism contrasts with eukaryotic or viral fusion systems that are either composed of multiple proteins or use a change in pH to initiate membrane fusion. Thus, our study demonstrates that Chlamydia-mediated membrane fusion is primarily regulated by specific structural domains in IncA and its local organization on the inclusion membrane, which is affected by the host cell lipid composition.
细胞内细菌病原体沙眼衣原体在称为包含体的膜结合隔室内复制。在感染几种衣原体后，每个细菌都会创建自己的包含体，从而导致每个宿主细胞内有多个包含体。最终，这些包含体在需要衣原体蛋白 IncA 的过程中融合在一起。在这里，我们表明融合前包含体形成独特的接触位点（包含体接触位点，ICSs），作为融合的平台，其中特定的脂质和衣原体蛋白集中。融合取决于 ICS 内 IncA 的聚类，并且受到 PI(3,4)P 和鞘脂的调节。随着 IncA 在 ICS 内浓缩，其 C 末端可能与对面膜上的 IncA 发生反式相互作用，从而确保融合部位的 IncA 浓度很高。这种调节机制与真核或病毒融合系统形成对比，后者要么由多个蛋白组成，要么利用 pH 值的变化来启动膜融合。因此，我们的研究表明，衣原体介导的膜融合主要受 IncA 的特定结构域及其在包含体膜上的局部组织的调节，而这又受宿主细胞脂质组成的影响。
