IDR-driven TOLLIP condensates antagonize the innate antiviral immunity by promoting the deSUMOylation of MAVS

Mitochondrial antiviral signaling protein (MAVS) is a central adaptor protein in retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling against RNA viral infection. Posttranslational modifications (PTMs) play a critical role in modulating the activity of MAVS. However, how phase separation regulates the PTMs to fine-tune MAVS activation remains to be elucidated. In this study, we identify Toll-interacting protein (TOLLIP) as a negative regulator of RLR signaling. A deficiency of TOLLIP leads to an enhanced type I interferon response upon RNA viral infection. Mice with the deletion of TOLLIP are more resistant to lethal vesicular stomatitis virus (VSV) infection than wild-type counterparts. Mechanistically, TOLLIP forms condensates that rely on its intrinsically disordered region (IDR). TOLLIP condensates interact with SENP1, promote the aggregation of SENP1, and enhance the interaction between SENP1 and MAVS, consequently leading to deSUMOylation and less aggregation of MAVS. Overall, our study reveals the critical role of TOLLIP condensation in regulating the activation of MAVS, emphasizing the complexity of MAVS activity modulation.