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.
Original language | English (US) |
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Pages (from-to) | 578-580 |
Number of pages | 3 |
Journal | Autophagy |
Volume | 17 |
Issue number | 2 |
DOIs | |
State | Published - 2021 |
Externally published | Yes |
Keywords
- Autoimmunity
- DAMPs
- IRGM
- IRGM1
- RIG-I-MAVS
- autophagy
- cGAS-STING
- mitophagy
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology