Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
PLoS Pathog. 2019 Mar 18;15(3):e1007684. doi: 10.1371/journal.ppat.1007684. eCollection 2019 Mar.
Phagocytosis is a complex process that eliminates microbes and is performed by specialised cells such as macrophages. Toll-like receptor 4 (TLR4) is expressed on the surface of macrophages and recognizes Gram-negative bacteria. Moreover, TLR4 has been suggested to play a role in the phagocytosis of Gram-negative bacteria, but the mechanisms remain unclear. Here we have used primary human macrophages and engineered THP-1 monocytes to show that the TLR4 sorting adapter, TRAM, is instrumental for phagocytosis of Escherichia coli as well as Staphylococcus aureus. We find that TRAM forms a complex with Rab11 family interacting protein 2 (FIP2) that is recruited to the phagocytic cups of E. coli. This promotes activation of the actin-regulatory GTPases Rac1 and Cdc42. Our results show that FIP2 guided TRAM recruitment orchestrates actin remodelling and IRF3 activation, two events that are both required for phagocytosis of Gram-negative bacteria.
吞噬作用是一种复杂的过程，可消除微生物，并由专门的细胞（如巨噬细胞）执行。Toll 样受体 4（TLR4）表达在巨噬细胞的表面，可识别革兰氏阴性菌。此外，TLR4 被认为在吞噬革兰氏阴性菌中发挥作用，但机制尚不清楚。在这里，我们使用原代人巨噬细胞和工程化 THP-1 单核细胞表明，TLR4 分拣衔接蛋白 TRAM 对于吞噬大肠杆菌和金黄色葡萄球菌至关重要。我们发现，TRAM 与 Rab11 家族相互作用蛋白 2（FIP2）形成复合物，该复合物被招募到大肠杆菌的吞噬杯中。这促进了肌动蛋白调节 GTPase Rac1 和 Cdc42 的激活。我们的结果表明，FIP2 指导的 TRAM 募集协调肌动蛋白重塑和 IRF3 激活，这两个事件都是吞噬革兰氏阴性菌所必需的。
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