ORMDL3 restrains type-I interferon signaling and anti-tumor immunity by promoting RIG-I degradation

Mounting evidence showed that the genetic association of ORMDL3 (ORMDL Sphingolipid Biosynthesis Regulator 3) gene polymorphisms with bronchial asthma and various inflammatory disorders. Yet its role in type I interferon (IFN) signaling remains poorly defined. Herein, we report that ORMDL3 is a negative modulator of the type I IFN signaling by engaging in an interaction with MAVS (Mitochondrial Antiviral Signaling protein) and subsequently directing RIG-I (Retinoic Acid-Inducible Gene I) for proteasome-mediated degradation. Immunoprecipitation coupled with mass spectrometry (IP-MS) assays uncovered that ORMDL3 binds to USP10 (Ubiquitin-Specific Protease 10), which forms a complex with and stabilizes RIG-I through decreasing its K48-linked ubiquitination. ORMDL3 thus disrupts the interaction between USP10 and RIG-I, thereby promoting RIG-I degradation. Additionally, subcutaneous syngeneic tumor models in C57BL/6 mice revealed that inhibition of ORMDL3 enhances anti-tumor efficacy by augmenting the proportion of cytotoxic CD8 positive T cells and IFN production in the tumor microenvironment (TME). Collectively, our findings reveal the pivotal roles of ORMDL3 in the maintenance of antiviral innate immune responses and anti-tumor immunity.