Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, 31077 Toulouse, France.
University of Lyon, Université Claude Bernard Lyon 1, 69100 Villeurbanne, France.
Cells. 2020 Mar 9;9(3):666. doi: 10.3390/cells9030666.
Autophagy is an important innate immune defense mechanism that controls () growth inside macrophages. Autophagy machinery targets -containing phagosomes via xenophagy after damage to the phagosomal membrane due to the Type VII secretion system Esx-1 or via LC3-associated phagocytosis without phagosomal damage. Conversely, restricts autophagy-related pathways via the production of various bacterial protein factors. Although bacterial lipids are known to play strategic functions in pathogenesis, their role in autophagy manipulation remains largely unexplored. Here, we report that the lipid virulence factors sulfoglycolipids (SLs) and phthiocerol dimycocerosates (DIMs) control autophagy-related pathways through distinct mechanisms in human macrophages. Using knock-out and knock-in mutants of and BCG (Bacille Calmette Guerin) and purified lipids, we found that (i) mutants with DIM and SL deficiencies promoted functional autophagy via an MyD88-dependent and phagosomal damage-independent pathway in human macrophages; (ii) SLs limited this pathway by acting as TLR2 antagonists; (iii) DIMs prevented phagosomal damage-independent autophagy while promoting Esx-1-dependent xenophagy; (iv) and DIMs, but not SLs, limited the acidification of LC3-positive compartments. In total, our study reveals an unexpected and intricate role for lipid virulence factors in controlling autophagy-related pathways in human macrophages, thus providing further insight into the autophagy manipulation tactics deployed by intracellular bacterial pathogens.
自噬是一种重要的先天免疫防御机制，可控制巨噬细胞内的 () 生长。自噬机制通过吞噬体膜因 VII 型分泌系统 Esx-1 而受损后的异噬作用，或通过无吞噬体损伤的 LC3 相关吞噬作用，靶向含有 () 的吞噬体。相反，通过产生各种细菌蛋白因子来限制与自噬相关的途径。尽管已知细菌脂质在发病机制中发挥战略作用，但它们在自噬操纵中的作用在很大程度上仍未得到探索。在这里，我们报告脂质毒力因子硫苷脂 (SLs) 和 phthiocerol dimycocerosates (DIMs) 通过人类巨噬细胞中不同的机制控制与自噬相关的途径。使用 SL 和 DIM 缺陷的 和 BCG（卡介苗）敲除和敲入突变体以及纯化的脂质，我们发现：(i) 缺乏 DIM 和 SL 的突变体通过人巨噬细胞中 MyD88 依赖性和吞噬体损伤非依赖性途径促进功能性自噬；(ii) SLs 通过作为 TLR2 拮抗剂限制该途径；(iii) DIMs 阻止吞噬体损伤非依赖性自噬，同时促进依赖 Esx-1 的异噬作用；(iv) 并且 DIMs 而不是 SLs 限制了 LC3 阳性 隔室的酸化。总的来说，我们的研究揭示了 脂质毒力因子在控制人类巨噬细胞中与自噬相关途径中的意外而复杂的作用，从而进一步深入了解细胞内细菌病原体所采用的自噬操纵策略。
