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Autoimmunity gene IRGM suppresses cGAS ‐ STING and RIG ‐I‐ MAVS signaling to control interferon response
Author(s) -
Jena Kautilya Kumar,
Mehto Subhash,
Nath Parej,
Chauhan Nishant Ranjan,
Sahu Rinku,
Dhar Kollori,
Das Saroj Kumar,
Kolapalli Srinivasa Prasad,
Murmu Krushna C,
Jain Ashish,
Krishna Sivaram,
Sahoo Bhabani Sankar,
Chattopadhyay Soma,
Rusten Tor Erik,
Prasad Punit,
Chauhan Swati,
Chauhan Santosh
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202050051
Subject(s) - innate immune system , immune system , biology , immunology
Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid‐sensing pathways leading to interferon‐stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG ‐I, and mediates their p62‐dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMP s and mt ROS . Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS ‐ STING and RIG ‐I‐ MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.