GGNBP2 regulates MDA5 sensing triggered by self double-stranded RNA following loss of ADAR1 editing
Adenosine-to-inosine (A-to-I) editing of double-stranded RNA (dsRNA) by ADAR1 is an essential modifier of the immunogenicity of cellular dsRNA. The role of MDA5 in sensing unedited cellular dsRNA and the downstream activation of type I interferon (IFN) signaling are well established. However, we have an incomplete understanding of pathways that modify the response to unedited dsRNA. We performed a genome-wide CRISPR screen and showed that GGNBP2, CNOT10, and CNOT11 interact and regulate sensing of unedited cellular dsRNA. We found that GGNBP2 acts between dsRNA transcription and its cytoplasmic sensing by MDA5. GGNBP2 loss prevented induction of type I IFN and autoinflammation after the loss of ADAR1 editing activity by modifying the subcellular distribution of endogenous A-to-I editing substrates and reducing cytoplasmic dsRNA load. These findings reveal previously undescribed pathways to modify diseases associated with <i>ADAR</i> mutations and may be determinants of response or resistance to small-molecule ADAR1 inhibitors.
Authors
- Ankita Goradia
- Diana Guallar
- Jacki Heraud-Farlow (ORCID: https://orcid.org/0000-0002-3786-8474)
- Alistair M. Chalk (ORCID: https://orcid.org/0000-0002-9630-6236)
- Carl R. Walkley (ORCID: https://orcid.org/0000-0002-4784-9031)
- Shi-Bin Hu (ORCID: https://orcid.org/0000-0002-3326-7890)
- Scott Taylor (ORCID: https://orcid.org/0000-0003-3394-1811)
- Iva Nikolić (ORCID: https://orcid.org/0000-0002-0141-5975)
- Kaylene J. Simpson (ORCID: https://orcid.org/0000-0001-9136-1781)
- Miguel Fidalgo (ORCID: https://orcid.org/0000-0003-1134-2674)
- Tao Sun (ORCID: https://orcid.org/0000-0002-2800-0921)
- Adriana Escudero (ORCID: https://orcid.org/0000-0003-3655-8893)
- Jin Billy Li (ORCID: https://orcid.org/0000-0003-0713-1399)
- Qin Li (ORCID: https://orcid.org/0000-0002-8948-2717)
Institutions
- Peter MacCallum Cancer Centre (AU)
- Hudson Institute of Medical Research (AU)
- St Vincent's Hospital Melbourne (AU)
- Victorian Comprehensive Cancer Centre (AU)
- Center for Research in Molecular Medicine and Chronic Diseases (ES)
- Monash University (AU)
- St Vincents Institute of Medical Research (AU)
- Stanford University (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2024-11-22
- DOI
- https://doi.org/10.1126/sciimmunol.adk0412
- Citations
- 9
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 2.10