Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Pharmaceutical biochemistry, School of pharmaceutical sciences, University of Geneva, Geneva, Switzerland.
PLoS One. 2024 Aug 26;19(8):e0309327. doi: 10.1371/journal.pone.0309327. eCollection 2024.
Phagocytic cells of the mammalian innate immune system play a critical role in protecting the body from bacterial infections. The multiple facets of this encounter (chemotaxis, phagocytosis, destruction, evasion and pathogenicity) are largely recapitulated in the phagocytic amoeba Dictyostelium discoideum. Here we identified a new chemical compound (K14; ZINC19168591) which inhibited intracellular destruction of ingested K. pneumoniae in D. discoideum cells. Concomitantly, K14 reduced proteolytic activity in D. discoideum phagosomes. In kil1 KO cells, K14 lost its ability to inhibit phagosomal proteolysis and to inhibit intra-phagosomal bacterial destruction, suggesting that K14 inhibits a Kil1-dependent protease involved in bacterial destruction. These observations stress the key role that proteases play in bacterial destruction. They also reveal an unsuspected link between Kil1 and phagosomal proteases. K14 can be used in the future as a tool to probe the role of different proteases in phagosomal physiology and in the destruction of ingested bacteria.
哺乳动物先天免疫系统的吞噬细胞在保护机体免受细菌感染方面发挥着关键作用。吞噬变形虫（Dictyostelium discoideum）在很大程度上重现了这种吞噬作用的多个方面（趋化性、吞噬作用、破坏、逃避和致病性）。在这里，我们鉴定出一种新的化学化合物（K14；ZINC19168591），它可以抑制 D. discoideum 细胞中摄入的肺炎克雷伯菌的细胞内破坏。同时，K14 降低了 D. discoideum 吞噬体中的蛋白水解活性。在 kil1 KO 细胞中，K14 丧失了抑制吞噬体蛋白水解和抑制吞噬体内细菌破坏的能力，这表明 K14 抑制了一种依赖 Kil1 的参与细菌破坏的蛋白酶。这些观察结果强调了蛋白酶在细菌破坏中的关键作用。它们还揭示了 Kil1 和吞噬体蛋白酶之间的一个意想不到的联系。K14 将来可被用作研究不同蛋白酶在吞噬体生理学和吞噬细菌中的作用的工具。
