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

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

doi:10.15252/embr.202050051

Abstract

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.

Highlights

Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases
A closer look at the genes and the pathways that are upregulated suggest that Immunity Related GTPase M (IRGM) deficiency results in the induction of interferon responses or the processes/ pathways controlled by the interferon responses (Figs 1A and EV1B, Appendix Fig S1B, Dataset EV1)
Almost all wellknown interferon-stimulated genes (ISGs) including interferon-inducible (IFI) genes, oligoadenylate synthases (OAS) genes, ISG15/20, guanylate-binding proteins (GBPs), apolipoprotein B mRNA-editing catalytic polypeptide-like genes (APOBEC), myxovirus resistance (MX genes), MHC class 1 antigen processing and presentation genes, and tripartite motif (TRIM) genes were upregulated upon knocking down IRGM (Fig 1A, and Dataset EV1)

Summary

Introduction

Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. 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. 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. IRGM deficiency increases the levels of the sensors, and 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. This study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases

Methods

Results

Conclusion