TY - JOUR
T1 - The p150 isoform of ADAR1 blocks sustained RLR signaling and apoptosis during influenza virus infection
AU - Vogel, Olivia A.
AU - Han, Julianna
AU - Liang, Chieh Yu
AU - Manicassamy, Santhakumar
AU - Perez, Jasmine T.
AU - Manicassamy, Balaji
N1 - Funding Information:
Olivia Vogel and Julianna Han were partly supported by the NIH Molecular and Cellular Biology training program at The University of Chicago (T32GM007183); Julianna Han was partly supported the NIH Diversity Supplement (R01AI123359- 02S1). Dr. Balaji Manicassamy is supported by NIAID grants (R01AI123359 and R01AI127775). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
Copyright: © 2020 Vogel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/9
Y1 - 2020/9
N2 - Signaling through retinoic acid inducible gene I (RIG-I) like receptors (RLRs) is tightly regulated, with activation occurring upon sensing of viral nucleic acids, and suppression mediated by negative regulators. Under homeostatic conditions aberrant activation of melanoma differentiation-associated protein-5 (MDA5) is prevented through editing of endogenous dsRNA by RNA editing enzyme Adenosine Deaminase Acting on RNA (ADAR1). In addition, ADAR1 is postulated to play pro-viral and antiviral roles during viral infections that are dependent or independent of RNA editing activity. Here, we investigated the importance of ADAR1 isoforms in modulating influenza A virus (IAV) replication and revealed the opposing roles for ADAR1 isoforms, with the nuclear p110 isoform restricting versus the cytoplasmic p150 isoform promoting IAV replication. Importantly, we demonstrate that p150 is critical for preventing sustained RIG-I signaling, as p150 deficient cells showed increased IFN-β expression and apoptosis during IAV infection, independent of RNA editing activity. Taken together, the p150 isoform of ADAR1 is important for preventing sustained RIG-I induced IFN-β expression and apoptosis during viral infection.
AB - Signaling through retinoic acid inducible gene I (RIG-I) like receptors (RLRs) is tightly regulated, with activation occurring upon sensing of viral nucleic acids, and suppression mediated by negative regulators. Under homeostatic conditions aberrant activation of melanoma differentiation-associated protein-5 (MDA5) is prevented through editing of endogenous dsRNA by RNA editing enzyme Adenosine Deaminase Acting on RNA (ADAR1). In addition, ADAR1 is postulated to play pro-viral and antiviral roles during viral infections that are dependent or independent of RNA editing activity. Here, we investigated the importance of ADAR1 isoforms in modulating influenza A virus (IAV) replication and revealed the opposing roles for ADAR1 isoforms, with the nuclear p110 isoform restricting versus the cytoplasmic p150 isoform promoting IAV replication. Importantly, we demonstrate that p150 is critical for preventing sustained RIG-I signaling, as p150 deficient cells showed increased IFN-β expression and apoptosis during IAV infection, independent of RNA editing activity. Taken together, the p150 isoform of ADAR1 is important for preventing sustained RIG-I induced IFN-β expression and apoptosis during viral infection.
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U2 - 10.1371/JOURNAL.PPAT.1008842
DO - 10.1371/JOURNAL.PPAT.1008842
M3 - Article
C2 - 32898178
AN - SCOPUS:85091266377
SN - 1553-7366
VL - 16
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 9
M1 - e1008842
ER -