GGNBP2 regulates MDA5 sensing triggered by self double-stranded RNA following loss of ADAR1 editing

Sci Immunol. 2024 Nov 22;9(101):eadk0412. doi: 10.1126/sciimmunol.adk0412. Epub 2024 Nov 22.

Abstract

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 ADAR mutations and may be determinants of response or resistance to small-molecule ADAR1 inhibitors.

MeSH terms

  • Adenosine Deaminase* / genetics
  • Adenosine Deaminase* / immunology
  • Animals
  • HEK293 Cells
  • Humans
  • Interferon Type I / immunology
  • Interferon-Induced Helicase, IFIH1* / genetics
  • Interferon-Induced Helicase, IFIH1* / immunology
  • Interferon-Induced Helicase, IFIH1* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • RNA Editing* / genetics
  • RNA, Double-Stranded* / genetics
  • RNA, Double-Stranded* / immunology
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / immunology

Substances

  • Adenosine Deaminase
  • Interferon-Induced Helicase, IFIH1
  • RNA, Double-Stranded
  • RNA-Binding Proteins
  • IFIH1 protein, human
  • ADAR protein, human
  • ADAR1 protein, mouse
  • Interferon Type I