Inflammatory bowel disease (IBD) is closely associated with dysregulation of genetic factors and microbial environment. Here, we report a susceptible role of ubiquitin-specific protease 2 (USP2) in experimental colitis and bacterial infections. USP2 is upregulated in the inflamed mucosa of IBD patients and in the colon of mice treated with dextran sulfate sodium salt (DSS). Knockout or pharmacologic inhibition of USP2 promotes the proliferation of myeloid cells to activate IL-22 and IFNgamma production of T cells. In addition, knockout of USP2 in myeloid cells inhibits the production of pro-inflammatory cytokines to relieve the dysregulation of extracellular matrix (ECM) network and promote the gut epithelial integrity after DSS treatment. Consistently, Lyz2-Cre;Usp2fl/fl mice exhibit hyper-resistance to DSS-induced colitis and Citrobacter rodentium infections compared to Usp2fl/fl mice. These findings highlight an indispensable role of USP2 in myeloid cells to modulate T cell activation and epithelial ECM network and repair, indicating USP2 as a potential target for therapeutic intervention of IBD and bacterial infections in the gastrointestinal system.

Mediator of IRF3 activation (MITA, also known as stimulator of interferon genes (STING) and endoplasmic reticulum interferon stimulator (ERIS)) is an ER-associated protein that senses cellular and bacterium-derived cyclic dinucleotide (CDN), leading to induction of type-I interferons (IFNs) and innate immune responses against viruses and bacteria. Recently, it has become clear that sensing of CDN and induction of autophagy are two evolutionarily conserved functions of MITA, predating its role in mediating type-I IFN induction. Studies have shown that MITA-mediated signaling promotes a number of autoimmune disorders caused by gene mutations in human. Here, we summarize the most recent progress on MITA-mediated signaling in a view of evolution and highlight the roles of MITA in human inflammatory disorders caused by gene mutations and in genetically modified mouse models. We also briefly introduce the chemicals targeting MITA and discuss their potential in treatment of MITA-mediated inflammatory diseases. Finally, we propose several key questions that should be addressed for targeting MITA for treatment of related autoimmune diseases.

The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays a critical role in antiviral immunity and autoimmunity. The activity and stability of cGAS are fine-tuned by post-translational modifications. Here, we show that ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) catalyzes the mono-ISGylation and induces the oligomerization of cGAS, thereby promoting antiviral immunity and autoimmunity. Knockdown or knockout of ARIH1 significantly inhibits herpes simplex virus 1 (HSV-1)- or cytoplasmic DNA-induced expression of type I interferons (IFNs) and proinflammatory cytokines. Consistently, tamoxifen-treated ER-Cre;Arih1(fl/fl) mice and Lyz2-Cre; Arih1(fl/fl) mice are hypersensitive to HSV-1 infection compared with the controls. In addition, deletion of ARIH1 in myeloid cells alleviates the autoimmune phenotypes and completely rescues the autoimmune lethality caused by TREX1 deficiency. Mechanistically, HSV-1- or cytosolic DNA-induced oligomerization and activation of cGAS are potentiated by ISGylation at its K187 residue, which is catalyzed by ARIH1. Our findings thus reveal an important role of ARIH1 in innate antiviral and autoimmune responses and provide insight into the post-translational regulation of cGAS.