RTN3 inhibits RIGI-I-mediated antiviral responses by impairing TRIM25-mediated K63-linked polyubiquitination

Abstract

Upon viral RNA recognition, the RIG-I signalosome continuously generates IFNs and cytokines, leading to neutrophil recruitment and inflammation. Thus, attenuation of excessive immune and inflammatory responses is crucial to restore immune homeostasis and prevent unwarranted damage, yet few proresolving mediators have been identified. In the present study, we demonstrated that RTN3 is strongly upregulated during RNA viral infection and acts as an inflammation-resolving regulator. Increased RTN3 aggregates on the endoplasmic reticulum and interacts with both TRIM25 and RIG-I, subsequently impairing K63-linked polyubiquitination and resulting in both IRF3 and NF-{kappa}B inhibition. Rtn3 overexpression in mice causes an obvious inflammation resolving phenomenon when challenged with VSV, Rtn3-overexpressing mice display significantly decreased neutrophil numbers and inflammatory cell infiltration, which is accompanied by reduced tissue edema in the liver and thinner alveolar interstitium. Taken together, our findings identify RTN3 as a conserved proresolving mediator of immune and inflammatory responses and provide insights into the negative feedback that maintains immune and inflammatory homeostasis. SummaryRTN3 is upregulated upon RNA viral infection due to inflammation and ER stress, in turn suppresses antiviral responses by impairing TRIM25-mediated RIG-I K63-linked polyubiquitination and consequently decreases neutrophil populations and inflammatory infiltration, representing a novel mechanism of negative inflammatory resolution.