Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 48, Pages 24974-24985Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.737098
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Funding
- Program of 1000 Young Talents
- National Natural Science Foundation of China [31370873, 31570865, 31600695]
- Jiangsu Provincial Distinguished Young Scholars Grant [BK20130004]
- Jiangsu Provincial Innovative Research Team
- Changjiang Scholars and Innovative Research Team, University of Ministry of Education of China [PCSIRT-IRT1075]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
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Adenosine deaminase acting on RNA 1 (ADAR1) catalyzes RNA editing of cellular and viral RNAs. Besides RNA editing, ADAR1 has recently been shown to play important roles in maintaining the body balance, including tissue homoeostasis, organ development, and autoimmune regulations, by inhibiting both IFN production and subsequent IFN-activated pathways. Accordingly, the question was raised how IFN signaling induced by viral infections overcomes the inhibitory effect of constitutively expressed ADAR1 (ADAR1-P110) to execute efficient antiviral activity. Here we unexpectedly found that IFN signaling promoted Lys(48)-linked ubiquitination and degradation of ADAR1-P110. Furthermore, we identified the E3 ligase beta transducin repeat-containing protein responsible for IFN-mediated ADAR1-P110 down-regulation. IFN signaling promoted the interaction between beta transducin repeat-containing protein and ADAR1-P110 as well as protein turnover of ADAR1-P110. Moreover, we found that both lysine 574 and 576 are essential for ADAR1-P110 ubiquitination. Critically, we demonstrated that down-regulation of ADAR1-P110 is required for IFN signaling to execute efficient antiviral activity during viral infections. These findings renew the understanding of the mechanisms by which IFN signaling acts to achieve antiviral functions and may provide potential targets for IFN-based antiviral therapy.
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