Inhibition of IRGM establishes a robust antiviral immune state to restrict pathogenic viruses

Abstract

The type I interferon (IFN) response is the major host arsenal against invading viruses. IRGM is a negative regulator of IFN responses under basal conditions. However, the role of human IRGM during viral infection has remained unclear. In this study, we show that IRGM expression is increased upon viral infection. IFN responses induced by viral PAMPs are negatively regulated by IRGM. Conversely, IRGM depletion results in a robust induction of key viral restriction factors including IFITMs, APOBECs, SAMHD1, tetherin, viperin, and HERC5/6. Additionally, antiviral processes such as MHC‐I antigen presentation and stress granule signaling are enhanced in IRGM‐deficient cells, indicating a robust cell‐intrinsic antiviral immune state. Consistently, IRGM‐depleted cells are resistant to the infection with seven viruses from five different families, including Togaviridae, Herpesviridae, Flaviviverdae, Rhabdoviridae, and Coronaviridae. Moreover, we show that Irgm1 knockout mice are highly resistant to chikungunya virus (CHIKV) infection. Altogether, our work highlights IRGM as a broad therapeutic target to promote defense against a large number of human viruses, including SARS‐CoV‐2, CHIKV, and Zika virus.

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“…TANK-binding kinase 1 ( TBK1 ) is a Ser/Thr kinase with a central role in coordinating the cellular response to invading pathogens and regulating key inflammatory signaling cascades. Some genes play an important role in the antiviral mechanism of cells, such as TBK1 , IRGM and so on ( 60 , 61 ). Studies have shown that TBK1 is also associated with cancers, such as kidney cancer, cervical cancer, and lung cancer ( 62 – 64 ).…”

MBZM-N-IBT, a Novel Small Molecule, Restricts Chikungunya Virus Infection by Targeting nsP2 Protease Activity In Vitro , In Vivo , and Ex Vivo

“…For this study, all mice were monitored every day up to 8 dpi. According to the symptom-based disease outcomes (no symptoms, 0; fur rise, 1; hunchback, 2; one hind limb paralysis, 3; both hind limb paralysis, 4; and death, 5), the clinical scores of each mice were tabulated on daily basis for the survival curve analysis ( 56 , 58 , 61 ).…”

Immunity-related GTPase IRGM at the intersection of autophagy, inflammation, and tumorigenesis

“…IRGM is also a fundamental negative regulator of type-1 IFN response against viral pathogens [21,55]. IRGM plays a key role in replication of HCV, an important risk factor for hepatocellular carcinoma, by regulating Golgi fragmentation and leading to co-localization of Golgi vesicles with replicating HCV [48].…”

“…This may aid in viral survival by autophagic degradation of nucleic acid-sensing proteins RIG-I and cGAS [21]. Epithelial and monocytic cells lines with abolished IRGM demonstrate enhanced antiviral properties, including MHC-I presentation and PKR stress granule formation, and are resistant to ZIKV and SARS-CoV-2 infection [55].…”