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

Ziwei Yang,Bailin He,Ersheng Kuang,Jun Wang,Xiaojuan Li,Xiaolin Zhang

doi:10.7554/elife.68958

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 resolving 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-κB 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 negative regulator of immune and inflammatory responses and provide insights into the negative feedback that maintains immune and inflammatory homeostasis.

Highlights

The innate immune responses can be triggered by pathogen-associated molecular patterns (PAMPs) and serve as the first line of defense against invading pathogens 1
RTN3 is upregulated upon RNA viral infection due to inflammation and endoplasmic reticulum (ER) stress, in turn suppresses antiviral responses by impairing tripartite motif-containing protein 25 (TRIM25)-mediated RIG-I K63-linked polyubiquitination and decreases neutrophil populations and inflammatory infiltration, representing a novel mechanism of negative inflammatory resolution
Rtn3 overexpression in mice causes an obvious inflammation resolving phenomenon when challenged with vesicular stomatitis virus (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

Summary

Introduction

The innate immune responses can be triggered by pathogen-associated molecular patterns (PAMPs) and serve as the first line of defense against invading pathogens 1. Pattern recognition receptors (PRRs) detect viral RNA, DNA and other viral products and subsequently mediate the activation of downstream signaling pathways 2 3. Both RIG-I and MDA5, two crucial members of the RIG-I-like receptor (RLR) family, sense cytoplasmic viral RNA and activate antiviral responses. Both RIG-I and MDA5 share the same domain architecture, comprising two N-terminal caspase activation recruitment domains (CARDs), a central DEAD box helicase/ATPase domain and a C-terminal regulatory domain (CTD) 3. The CARD domain recruits MAVS and activates the downstream signaling cascade to induce the expression of type I interferons, IFN stimulated genes (ISGs), inflammatory cytokines and/or chemokines 7

Methods

Results

Discussion

Conclusion