Autoimmunity gene IRGM suppresses cGAS-STING and RIG-I-MAVS signaling to control interferon response

Kautilya Kumar Jena, Subhash Mehto, Parej Nath, Nishant Ranjan Chauhan, Rinku Sahu, Kollori Dhar, Saroj Kumar Das, Srinivasa Prasad Kolapalli, Krushna C. Murmu, Ashish Jain, Sivaram Krishna, Bhabani Sankar Sahoo, Soma Chattopadhyay, Tor Erik Rusten, Punit Prasad, Swati Chauhan, Santosh Chauhan

Research output: Contribution to journalArticlepeer-review


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 DAMPs and mtROS. 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.

Original languageEnglish (US)
Article numbere50051
JournalEMBO reports
Issue number9
StatePublished - Sep 3 2020
Externally publishedYes


  • IRGM
  • autophagy
  • mitophagy

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics


Dive into the research topics of 'Autoimmunity gene IRGM suppresses cGAS-STING and RIG-I-MAVS signaling to control interferon response'. Together they form a unique fingerprint.

Cite this