Section of Oral, Diagnostic and Rehabilitation Sciences, Division of Periodontics, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Department of Systems Biology, Vagelos College of physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
EMBO Rep. 2021 Jul 5;22(7):e52891. doi: 10.15252/embr.202152891. Epub 2021 Jun 29.
Fusobacterium nucleatum (Fn) is a Gram-negative oral commensal, prevalent in various human diseases. It is unknown how this common commensal converts to a rampant pathogen. We report that Fn secretes an adhesin (FadA) with amyloid properties via a Fap2-like autotransporter to enhance its virulence. The extracellular FadA binds Congo Red, Thioflavin-T, and antibodies raised against human amyloid β42. Fn produces amyloid-like FadA under stress and disease conditions, but not in healthy sites or tissues. It functions as a scaffold for biofilm formation, confers acid tolerance, and mediates Fn binding to host cells. Furthermore, amyloid-like FadA induces periodontal bone loss and promotes CRC progression in mice, with virulence attenuated by amyloid-binding compounds. The uncleaved signal peptide of FadA is required for the formation and stability of mature amyloid FadA fibrils. We propose a model in which hydrophobic signal peptides serve as "hooks" to crosslink neighboring FadA filaments to form a stable amyloid-like structure. Our study provides a potential mechanistic link between periodontal disease and CRC and suggests anti-amyloid therapies as possible interventions for Fn-mediated disease processes.
具核梭杆菌（Fn）是一种革兰氏阴性口腔共生菌，普遍存在于各种人类疾病中。目前尚不清楚这种常见共生菌如何转变为猖獗的病原体。我们报告称，Fn 通过类似于 Fap2 的自转运蛋白分泌具有淀粉样特性的黏附素（FadA），从而增强其毒力。细胞外的 FadA 与刚果红、硫黄素 T 和针对人淀粉样β42 的抗体结合。Fn 在应激和疾病条件下产生淀粉样 FadA，但在健康部位或组织中不产生。它作为生物膜形成的支架，赋予耐酸能力，并介导 Fn 与宿主细胞的结合。此外，淀粉样 FadA 诱导牙周骨丢失并促进小鼠 CRC 的进展，淀粉样结合化合物可减弱其毒力。FadA 的未切割信号肽是成熟淀粉样 FadA 纤维形成和稳定所必需的。我们提出了一个模型，其中疏水性信号肽充当“钩子”，将相邻的 FadA 纤维交联在一起，形成稳定的淀粉样结构。我们的研究为牙周病和 CRC 之间提供了一个潜在的机制联系，并表明抗淀粉样蛋白治疗可能是 Fn 介导的疾病过程的干预措施。
