The Unfolded-Protein Response Triggers the Arthropod Immune Deficiency Pathway.

The insect immune deficiency (IMD) pathway is a defense mechanism that senses and responds to Gram-negative bacteria. Ticks lack genes encoding upstream components that initiate the IMD pathway. Despite this deficiency, core signaling molecules are present and functionally restrict tick-borne pathogens. The molecular events preceding activation remain undefined. Here, we show that the unfolded-protein response (UPR) initiates the IMD network. The endoplasmic reticulum (ER) stress receptor IRE1α is phosphorylated in response to tick-borne bacteria but does not splice the mRNA encoding XBP1. Instead, through protein modeling and reciprocal pulldowns, we show that Ixodes IRE1α complexes with TRAF2. Disrupting IRE1α-TRAF2 signaling blocks IMD pathway activation and diminishes the production of reactive oxygen species. Through in vitro, in vivo, and ex vivo techniques, we demonstrate that the UPR-IMD pathway circuitry limits the Lyme disease-causing spirochete Borrelia burgdorferi and the rickettsial agents Anaplasma phagocytophilum and A. marginale (anaplasmosis). Altogether, our study uncovers a novel linkage between the UPR and the IMD pathway in arthropods.

昆虫免疫缺陷（IMD）通路是一种感知并响应革兰氏阴性细菌的防御机制。蜱缺乏编码启动IMD通路的上游组分的基因。尽管存在这种缺陷，但核心信号分子仍然存在，并在功能上限制蜱传病原体。激活前的分子事件仍未明确。在此，我们表明未折叠蛋白反应（UPR）启动了IMD网络。内质网（ER）应激受体IRE1α响应蜱传细菌而被磷酸化，但不会剪接编码XBP1的mRNA。相反，通过蛋白质建模和相互下拉实验，我们表明硬蜱IRE1α与TRAF2形成复合物。破坏IRE1α - TRAF2信号传导会阻断IMD通路的激活，并减少活性氧物质的产生。通过体外、体内和离体技术，我们证明UPR - IMD通路回路限制了导致莱姆病的螺旋体伯氏疏螺旋体以及立克次氏体病原体嗜吞噬细胞无形体和边缘无形体（无形体病）。总之，我们的研究揭示了节肢动物中UPR和IMD通路之间的一种新型联系。