SLIRP amplifies antiviral signaling via positive feedback regulation and contributes to autoimmune diseases
Abnormal innate immune response is a prominent feature underlying autoimmune diseases. One emerging factor driving 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 an amplifier of mt-dsRNA-triggered antiviral signals. In autoimmune diseases, SLIRP is commonly upregulated, and the 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 elevates their cytosolic levels to activate MDA5 further, augmenting the interferon response. Furthermore, the downregulation of SLIRP partially rescues the abnormal interferon-stimulated gene expression in primary cells of patients with autoimmune disease and makes cells vulnerable to certain viral infections. Our study unveils SLIRP as a pivotal mediator of the interferon response through positive feedback amplification of antiviral signaling via mt-dsRNAs.
Authors
- Namseok Lee (ORCID: https://orcid.org/0000-0002-3291-6561)
- Youngran Park (ORCID: https://orcid.org/0000-0002-8621-1399)
- Jae‐Seon Lee (ORCID: https://orcid.org/0000-0001-6002-5267)
- You‐Jung Ha (ORCID: https://orcid.org/0000-0001-6107-9523)
- Soojin Jang (ORCID: https://orcid.org/0000-0002-2921-7196)
- Daesong Jang
- Seunghee Cha (ORCID: https://orcid.org/0000-0003-3772-1832)
- Yun Jong Lee (ORCID: https://orcid.org/0000-0001-7615-8611)
- Doyeong Ku (ORCID: https://orcid.org/0000-0001-6037-0001)
- Keonyong Lee (ORCID: https://orcid.org/0000-0003-3285-1881)
- Yoosik Kim (ORCID: https://orcid.org/0000-0003-3064-4643)
- Se Rim Choi (ORCID: https://orcid.org/0000-0002-4625-8571)
- Yeon Bi Han (ORCID: https://orcid.org/0000-0002-3657-5012)
- Woo‐Jin Jeong (ORCID: https://orcid.org/0000-0001-8577-6964)
- Kyung‐Jin Lee (ORCID: https://orcid.org/0000-0001-6269-2266)
- Yong Seok Choi
- Yong-Ki Lee (ORCID: https://orcid.org/0000-0001-5976-3043)
- Yewon Yang
Institutions
- Seoul National University (KR)
- Korea Advanced Institute of Science and Technology (KR)
- Seoul National University Hospital (KR)
- Seoul National University Bundang Hospital (KR)
- Korea Food Research Institute (KR)
- Florida College (US)
- Center for Autism and Related Disorders (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-04-19
- DOI
- https://doi.org/10.1016/j.celrep.2025.115588
- Citations
- 2
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- Ministry of Health and Welfare
- National Institutes of Health
- National Institute of Dental and Craniofacial Research