Department of Oral Microbiology and Immunology, School of Dentistry, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea.
Department of Periodontology, Ajou University Hospital, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea.
Cell Death Differ. 2018 Feb;25(2):380-391. doi: 10.1038/cdd.2017.167. Epub 2017 Oct 27.
Caspase-4 is an inflammatory caspase; however, its mechanism of activation is poorly understood. In this study, we demonstrate that Td92, a surface protein of the periodontal pathogen Treponema denticola and a homolog of the Treponema pallidum surface protein Tp92, activates caspase-4 and induces pyroptosis in primary cultured human gingival fibroblasts (HGFs) via cathepsin G activation. Cathepsin G inhibition or siRNA knockdown of cathepsin G inhibited Td92-induced caspase-4 activation and cell death. Td92-induced cell death was significantly inhibited by siRNA knockdown of gasdermin D. Td92 treatment resulted in the binding of cathepsin G to caspase-4 and the coaggregation of these two molecules. In addition, Td92 induced IL-1α expression and secretion, and this was inhibited by caspase-4 knockdown. Cytochalasin D did not block Td92-induced caspase-4 activation, suggesting that Td92 internalization is not required for caspase-4 activation. Our results demonstrate that cathepsin G is directly engaged in caspase-4 activation by a bacterial ligand, which is responsible for cell death and IL-1α secretion in HGFs.
Caspase-4 是一种炎症 Caspase，但它的激活机制尚不清楚。在这项研究中，我们证明了 Td92，一种牙周病原体密螺旋体的表面蛋白，也是梅毒螺旋体表面蛋白 Tp92 的同源物，通过组织蛋白酶 G 的激活，激活 caspase-4 并诱导原代培养的人牙龈成纤维细胞（HGFs）发生细胞焦亡。组织蛋白酶 G 抑制或组织蛋白酶 G 的 siRNA 敲低抑制了 Td92 诱导的 caspase-4 激活和细胞死亡。Gasdermin D 的 siRNA 敲低显著抑制了 Td92 诱导的细胞死亡。Td92 处理导致组织蛋白酶 G 与 caspase-4 结合，以及这两种分子的共聚集。此外，Td92 诱导了 IL-1α 的表达和分泌，而 caspase-4 的敲低抑制了这一过程。细胞松弛素 D 并没有阻断 Td92 诱导的 caspase-4 激活，这表明 Td92 的内化对于 caspase-4 的激活不是必需的。我们的研究结果表明，组织蛋白酶 G 通过细菌配体直接参与 caspase-4 的激活，这是 HGFs 中细胞死亡和 IL-1α 分泌的原因。
