Abstract
RIG-I is a key cytosolic pattern recognition receptor that interacts with MAVS to induce type I interferons (IFNs) against RNA virus infection. In this study, we found that cyclophilin A (CypA), a peptidyl-prolyl cis/trans isomerase, functioned as a critical positive regulator of RIG-I-mediated antiviral immune responses. Deficiency of CypA impaired RIG-I-mediated type I IFN production and promoted viral replication in human cells and mice. Upon Sendai virus infection, CypA increased the interaction between RIG-I and its E3 ubiquitin ligase TRIM25, leading to enhanced TRIM25-mediated K63-linked ubiquitination of RIG-I that facilitated recruitment of RIG-I to MAVS. In addition, CypA and TRIM25 competitively interacted with MAVS, thereby inhibiting TRIM25-induced K48-linked ubiquitination of MAVS. Taken together, our findings reveal an essential role of CypA in boosting RIG-I-mediated antiviral immune responses by controlling the ubiquitination of RIG-I and MAVS.
Original language | English |
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Article number | e24425 |
Journal | eLife |
Volume | 6 |
DOIs | |
State | Published - Jun 8 2017 |
Keywords
- Adaptor Proteins, Signal Transducing/metabolism
- Animals
- Antiviral Agents/metabolism
- Cell Line
- Cyclophilin A/metabolism
- DEAD Box Protein 58/metabolism
- Humans
- Interferon Type I/metabolism
- Mice
- Receptors, Immunologic
- Sendai virus/immunology
- Transcription Factors/metabolism
- Tripartite Motif Proteins/metabolism
- Ubiquitin-Protein Ligases/metabolism
- Ubiquitination