INSERM, U1016, Institut Cochin, CNRS, UMR8104, Université de Paris, 22 rue Méchain, 75014, Paris, France.
Cell Mol Life Sci. 2021 Jan;78(1):17-29. doi: 10.1007/s00018-020-03577-w. Epub 2020 Jun 26.
The innate immune response constitutes the first line of defense against pathogens. It involves the recognition of pathogen-associated molecular patterns (PAMPs) by pathogen recognition receptors (PRRs), the production of inflammatory cytokines and the recruitment of immune cells to infection sites. Recently, ADP-heptose, a soluble intermediate of the lipopolysaccharide biosynthetic pathway in Gram-negative bacteria, has been identified by several research groups as a PAMP. Here, we recapitulate the evidence that led to this identification and discuss the controversy over the immunogenic properties of heptose 1,7-bisphosphate (HBP), another bacterial heptose previously defined as an activator of innate immunity. Then, we describe the mechanism of ADP-heptose sensing by alpha-protein kinase 1 (ALPK1) and its downstream signaling pathway that involves the proteins TIFA and TRAF6 and induces the activation of NF-κB and the secretion of inflammatory cytokines. Finally, we discuss possible delivery mechanisms of ADP-heptose in cells during infection, and propose new lines of thinking to further explore the roles of the ADP-heptose/ALPK1/TIFA axis in infections and its potential implication in the control of intestinal homeostasis.
先天免疫反应构成了抵御病原体的第一道防线。它涉及病原体识别受体 (PRR) 识别病原体相关分子模式 (PAMP)、炎症细胞因子的产生以及免疫细胞向感染部位的募集。最近，ADP-庚糖已被几个研究小组确定为 PAMP，它是革兰氏阴性菌脂多糖生物合成途径中的一种可溶性中间产物。在这里，我们回顾了导致这一鉴定的证据，并讨论了另一种细菌庚糖 1,7-双磷酸 (HBP) 的免疫原性特性的争议，HBP 此前被定义为先天免疫激活剂。然后，我们描述了 alpha-蛋白激酶 1 (ALPK1) 对 ADP-庚糖的感应机制及其下游信号通路，该通路涉及 TIFA 和 TRAF6 蛋白，并诱导 NF-κB 的激活和炎症细胞因子的分泌。最后，我们讨论了感染过程中细胞内 ADP-庚糖的可能传递机制，并提出了新的思路来进一步探索 ADP-庚糖/ALPK1/TIFA 轴在感染中的作用及其在控制肠道稳态中的潜在意义。
