ABSTRACT

IRGM is a genetic risk factor for several autoimmune diseases. However, the mechanism of IRGM-mediated protection in autoimmunity remains undetermined. The abnormal activation of type I interferon (IFN) response is one of the significant factors in the pathogenesis of several autoimmune diseases. In our recent study, we showed that IRGM is a master suppressor of the interferon response. We found that the depletion of IRGM results in constitutively activated CGAS-STING1, DDX58/RIG-I-MAVS, and TLR3-TICAM1/TRIF signaling pathways resulting in upregulation of almost all IFN-responsive genes. Mechanistically, IRGM utilizes a two-pronged mechanism to suppress the interferon response. First, it mediates SQSTM1/p62-dependent selective macroautophagy/autophagy of nucleic acid sensor proteins, including CGAS, DDX58/RIG-I, and TLR3. Second, it facilitates the removal of defective mitochondria by mitophagy and avoids a buildup of mito-ROS and mito-damage/danger-associated molecular patterns (DAMPs). Thus, IRGM deficiency results in increased nucleic acid sensors and DAMPs engaging a vicious cycle of aberrant activation of IFN response that is known to occur in systemic autoimmune-like conditions.

摘要

IRGM 是几种自身免疫性疾病的遗传风险因素。然而，IRGM 介导的自身免疫保护机制仍未确定。I型干扰素(IFN)反应的异常激活是几种自身免疫性疾病发病机制中的重要因素之一。在我们最近的研究中，我们表明 IRGM 是干扰素反应的主要抑制因子。我们发现 IRGM 的消耗导致组成型激活的 CGAS-STING1、DDX58/RIG-I-MAVS 和 TLR3-TICAM1/TRIF 信号通路导致几乎所有 IFN 反应基因的上调。从机制上讲，IRGM 利用双管齐下的机制来抑制干扰素反应。首先，它介导 SQSTM1/p62 依赖性选择性巨自噬/核酸传感器蛋白的自噬，包括 CGAS、DDX58/RIG-I 和 TLR3。第二，它有助于通过 mitophagy 去除有缺陷的线粒体，并避免 mito-ROS 和 mito 损伤/危险相关分子模式 (DAMP) 的积累。因此，IRGM 缺乏会导致核酸传感器和 DAMP 增加，从而导致 IFN 反应异常激活的恶性循环，已知这种反应发生在全身性自身免疫样疾病中。