Mentrup Torben, Stumpff-Niggemann Anna Yamina, Leinung Nadja, Schlosser Christine, Schubert Katja, Wehner Rebekka, Tunger Antje, Schatz Valentin, Neubert Patrick, Gradtke Ann-Christine, Wolf Janina, Rose-John Stefan, Saftig Paul, Dalpke Alexander, Jantsch Jonathan, Schmitz Marc, Fluhrer Regina, Jacobsen Ilse D, Schröder Bernd
Institute of Physiological Chemistry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Biochemical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany.
Nat Commun. 2022 Apr 6;13(1):1880. doi: 10.1038/s41467-022-29474-3.
Sensing of pathogens by pattern recognition receptors (PRR) is critical to initiate protective host defence reactions. However, activation of the immune system has to be carefully titrated to avoid tissue damage necessitating mechanisms to control and terminate PRR signalling. Dectin-1 is a PRR for fungal β-glucans on immune cells that is rapidly internalised after ligand-binding. Here, we demonstrate that pathogen recognition by the Dectin-1a isoform results in the formation of a stable receptor fragment devoid of the ligand binding domain. This fragment persists in phagosomal membranes and contributes to signal transduction which is terminated by the intramembrane proteases Signal Peptide Peptidase-like (SPPL) 2a and 2b. Consequently, immune cells lacking SPPL2b demonstrate increased anti-fungal ROS production, killing capacity and cytokine responses. The identified mechanism allows to uncouple the PRR signalling response from delivery of the pathogen to degradative compartments and identifies intramembrane proteases as part of a regulatory circuit to control anti-fungal immune responses.
模式识别受体（PRR）对病原体的感知对于启动宿主保护性防御反应至关重要。然而，免疫系统的激活必须精确调节，以避免组织损伤，这就需要控制和终止PRR信号传导的机制。Dectin-1是免疫细胞上真菌β-葡聚糖的PRR，在配体结合后会迅速内化。在此，我们证明Dectin-1a同种型对病原体的识别会导致形成一个缺乏配体结合域的稳定受体片段。该片段持续存在于吞噬体膜中，并有助于信号转导，而信号转导由膜内蛋白酶信号肽肽酶样（SPPL）2a和2b终止。因此，缺乏SPPL2b的免疫细胞表现出增强的抗真菌ROS产生、杀伤能力和细胞因子反应。所确定的机制使PRR信号反应与病原体向降解区室的传递解偶联，并将膜内蛋白酶确定为控制抗真菌免疫反应的调节回路的一部分。
