IRGM links autoimmunity to autophagy

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.

Keywords: Autoimmunity; DAMPs; IRGM; IRGM1; RIG-I-MAVS; autophagy; cGAS-STING; mitophagy.

Figure 1.

The model of IRGM linking autophagy and autoimmunity. In the absence of IRGM, selective autophagy of nucleic acid sensors and mitophagy are diminished, resulting in an increased amount of nucleic acid sensor proteins and the accumulation of DAMPs leading to a vicious cycle of inflammation. The DAMPs are sensed by the nucleic acid-sensing pathways to activate the IFN response and production of ISGs, which in turn induce other invasive/aggressive immune reactions leading to cell death, tissue/organ damage, and more DAMPs, culminating in autoimmune-like conditions