1. SLIRP promotes autoimmune diseases by amplifying antiviral signaling via positive feedback regulation.
- Author
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Ku D, Yang Y, Park Y, Jang D, Lee N, Lee YK, Lee K, Lee J, Han YB, Jang S, Choi SR, Ha YJ, Choi YS, Jeong WJ, Lee YJ, Lee KJ, Cha S, and Kim Y
- Abstract
The abnormal innate immune response is a prominent feature underlying autoimmune diseases. One emerging factor that can trigger dysregulated immune activation is cytosolic mitochondrial double-stranded RNAs (mt-dsRNAs). However, the mechanism by which mt-dsRNAs stimulate immune responses remains poorly understood. Here, we discover SRA stem-loop interacting RNA binding protein (SLIRP) as a key amplifier of mt-dsRNA-triggered antiviral signals. In autoimmune diseases, SLIRP is commonly upregulated, and targeted knockdown of SLIRP dampens the interferon response. We find that the activation of melanoma differentiation-associated gene 5 (MDA5) by exogenous dsRNAs upregulates SLIRP, which then stabilizes mt-dsRNAs and promotes their cytosolic release to activate MDA5 further, augmenting the interferon response. Furthermore, the downregulation of SLIRP partially rescues the abnormal interferon-stimulated gene expression in autoimmune patients' primary cells and makes cells vulnerable to certain viral infections. Our study unveils SLIRP as a pivotal mediator of interferon response through positive feedback amplification of antiviral signaling., Competing Interests: DECLARATION OF INTERESTS Jaeseon Lee, Soojin Jang, and Kyung Jin Lee are employees of ORGANOIDSCIENCES Ltd. Other authors have no conflict of interest to declare.
- Published
- 2024
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