TY - JOUR
T1 - RNase H2 catalytic core Aicardi-Goutières syndrome-Related mutant invokes cGAS-STING innate immunesensing pathway in mice
AU - Pokatayev, Vladislav
AU - Hasin, Naushaba
AU - Chon, Hyongi
AU - Cerritelli, Susana M.
AU - Sakhuja, Kiran
AU - Ward, Jerrold M.
AU - Douglas Morris, H.
AU - Yan, Nan
AU - Crouch, Robert J.
N1 - Funding Information:
This work is supported by grants from the National Institutes of Health (AI098569 and AR067135 to N. Yan), Alliance for Lupus Research (329774 N. Yan), UT Southwestern Immunology graduate program training grant (2T32AI005284 to V. Pokatayev), and in part by the Intramural Research Program of the National Institutes of Health.
Publisher Copyright:
© 2016 Pokatayev et al.
PY - 2016/3/7
Y1 - 2016/3/7
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20151464
DO - 10.1084/jem.20151464
M3 - Article
C2 - 26880576
AN - SCOPUS:84961214693
SN - 0022-1007
VL - 213
SP - 329
EP - 336
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 3
ER -