Signaling from the RNA sensor RIG-I is regulated by ufmylation

The RNA-binding protein RIG-I is a key initiator of the antiviral innate immune response. The signaling that mediates the antiviral response downstream of RIG-I is transduced through the adaptor protein MAYS and results in the induction of type I and III interferons (IFNs). This signal transduction occurs at endoplasmic reticulum (ER)-mitochondrial contact sites, to which RIG-I and other signaling proteins are recruited following their activation. RIG-I signaling is highly regulated to prevent aberrant activation of this pathway and dysregulated induction of IFN. Previously, we identified UFL1, the E3 ligase of the ubiquitin-like modifier conjugation system called ufmylation, as one of the proteins recruited to membranes at ER-mitochondrial contact sites in response to RIG-I activation. Here, we show that UFL1, as well as the process of ufmylation, promote IFN induction in response to RIG-I activation. We found that following RNA virus infection, UFL1 is recruited to the membrane-targeting protein 14-3-3e and that this complex is then recruited to activated RIG-I to promote downstream innate immune signaling. Importantly, we found that 14-3-3e has an increase in UFM1 conjugation following RIG-I activation. Additionally, loss of cellular ufmylation prevents the interaction of 14-3-3e with RIG-I, which abrogates the interaction of RIG-I with MAYS and thus the downstream signal transduction that induces IFN. Our results define ufmylation as an integral regulatory component of the RIG-I signaling pathway and as a posttranslational control for IFN induction.

Automated summary

The RNA-binding protein RIG-I plays a crucial role in initiating the innate immune response against viruses. In this study, the researchers found that a protein called UFL1, along with the process of ufmylation, promotes the induction of interferons in response to RIG-I activation. They also discovered that UFL1 interacts with the protein 14-3-3e at the cell membrane, and this complex is recruited to activated RIG-I to facilitate immune signaling. Furthermore, they found that ufmylation is necessary for the interaction between 14-3-3e and RIG-I, which is essential for downstream signal transduction and IFN induction.