RNase H2 catalytic core Aicardi-Goutières syndrome-Related mutant invokes cGAS-STING innate immunesensing pathway in mice

Vladislav Pokatayev, Naushaba Hasin, Hyongi Chon, Susana M. Cerritelli, Kiran Sakhuja, Jerrold M. Ward, H. Douglas Morris, Nan Yan, Robert J. Crouch

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Abstract

The neuroinflammatory autoimmune disease Aicardi-Goutières syndrome (AGS) develops from mutations in genes encoding several nucleotide-processing proteins, including RNase H2. Defective RNase H2 may induce accumulation of self-nucleic acid species that trigger chronic type I interferon and inflammatory responses, leading to AGS pathology. We created a knock-in mouse model with an RNase H2 AGS mutation in a highly conserved residue of the catalytic subunit, Rnaseh2aG37S/G37S (G37S), to understand disease pathology. G37S homozygotes are perinatal lethal, in contrast to the early embryonic lethality previously reported for Rnaseh2b- or Rnaseh2c-null mice. Importantly, we found that the G37S mutation led to increased expression of interferon-stimulated genes dependent on the cGAS-STI NG signaling pathway. Ablation of STI NG in the G37S mice results in partial rescue of the perinatal lethality, with viable mice exhibiting white spotting on their ventral surface. We believe that the G37S knock-in mouse provides an excellent animal model for studying RNA SEH2-associated autoimmune diseases.

Original languageEnglish (US)
Pages (from-to)329-336
Number of pages8
JournalJournal of Experimental Medicine
Volume213
Issue number3
DOIs
Publication statusPublished - 2016

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ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Pokatayev, V., Hasin, N., Chon, H., Cerritelli, S. M., Sakhuja, K., Ward, J. M., ... Crouch, R. J. (2016). RNase H2 catalytic core Aicardi-Goutières syndrome-Related mutant invokes cGAS-STING innate immunesensing pathway in mice. Journal of Experimental Medicine, 213(3), 329-336. https://doi.org/10.1084/jem.20151464