Bexkens Michiel L, Houweling Martin, Burgers Peter C, Luider Theo M, Tielens Aloysius G M, van Hellemond Jaap J
Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Chem Phys Lipids. 2020 Oct;232:104951. doi: 10.1016/j.chemphyslip.2020.104951. Epub 2020 Aug 12.
Toll-like receptor 2 (TLR2) is an important pattern recognition receptor on the surface of host immune cells that binds a variety of ligands that are released by microorganisms as well as by damaged or dying host cells. According to the current concept, TLR2/1 and TLR2/6 heterodimers are activated by tri- or di-acylated ligands, respectively. However, also mono-acyl phospholipid containing lipid fractions derived from parasites, were reported to be able to activate TLR2. In order to provide conclusive evidence for the TLR2 activating capacity of mono-acyl phospholipids derived from pathogens, we developed a biosynthetic method to enzymatically convert commercially available phospholipids into several mono-acyl-phospholipid variants that were examined for their TLR2 activating capacity. These investigations demonstrated that 1-(11Z-eicosenoyl)-glycero-3-phosphoserine 20:1 (20:1 lyso-PS) is a true agonist of the TLR2/6 heterodimer and that its polar headgroup as well as the length of the acyl chain are crucial for TLR2 activation. In silico modelling further confirmed 20:1 mono-acyl PS as a ligand for TLR2/6 heterodimer, as this predicted that multiple hydrogen bonds are formed between the polar headgroup of 20:1 mono-acyl PS and amino acid residues of both TLR2 and TLR6. Future studies can now be performed to further assess the functions of 20:1 lyso-PS as an immunological mediator, because this enzymatic method enables its preparation in larger quantities than is possible by isolation from the parasite that naturally produces this compound, Schistosoma mansoni, the source of the original discovery (Van der Kleij et al., 2002).
Toll样受体2（TLR2）是宿主免疫细胞表面一种重要的模式识别受体，可结合多种由微生物以及受损或濒死宿主细胞释放的配体。根据当前概念，TLR2/1和TLR2/6异二聚体分别由三酰化或二酰化配体激活。然而，据报道，来源于寄生虫的含单酰基磷脂的脂质组分也能够激活TLR2。为了提供病原体来源的单酰基磷脂激活TLR2能力的确凿证据，我们开发了一种生物合成方法，通过酶促将市售磷脂转化为几种单酰基磷脂变体，并检测它们激活TLR2的能力。这些研究表明，1-（11Z-二十碳烯酰基）-甘油-3-磷酸丝氨酸20:1（20:1溶血磷脂酰丝氨酸）是TLR2/6异二聚体的真正激动剂，其极性头部基团以及酰基链的长度对于TLR2激活至关重要。计算机模拟进一步证实20:1单酰基磷脂酰丝氨酸是TLR2/6异二聚体的配体，因为这预测20:1单酰基磷脂酰丝氨酸的极性头部基团与TLR2和TLR6的氨基酸残基之间形成了多个氢键。现在可以进行进一步的研究，以进一步评估20:1溶血磷脂酰丝氨酸作为免疫介质的功能，因为这种酶促方法能够大量制备该物质，比从最初发现该化合物的曼氏血吸虫（Van der Kleij等人，2002年）中分离制备的量更大。
