Su Jin Choi1,†, Hyun-Cheol Lee2,†, Jae-Hoon Kim2, Song Yi Park1, Tae-Hwan Kim2, Woon-Kyu Lee3, Duk-Jae Jang2, Ji-Eun Yoon4, Young-Il Choi5, Seihwan Kim5, JinYeul Ma6, Chul-Joong Kim2, Tso-Pang Yao7, Jae U Jung8, Joo-Yong Lee*,1 and Jong-Soo Lee*,2
1Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, Korea
2College of Veterinary Medicine (BK21 Plus Program), Chungnam National University, Daejeon, Korea
3College of Medicine, Inha University, Incheon, Korea
4Foot and Mouth Disease Division, Animal Quarantine and Inspection Agency, Anyang, Korea
5CKD Research Institute, Yongin-si Gyeonggi-do, Korea
6Korean Medicine (KM) Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, Daejeon, Korea
7Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
8Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
* Corresponding author : Joo-Yong Lee, Jong-Soo Lee
† These authors contributed equally to this work
Abstract
RIG-I is a key cytosolic sensor that detects RNA viruses through its C-terminal region and activates the production of antiviral interferons (IFNs) and proinflammatory cytokines. While posttranslational modification has been demonstrated to regulate RIG-I signaling activity, its significance for the sensing of viral RNAs remains unclear. Here, we first show that the RIG-I C-terminal region undergoes deacetylation to regulate its viral RNA-sensing activity and that the HDAC6-mediated deacetylation of RIG-I is critical for viral RNA detection. HDAC6 transiently bound to RIG-I and removed the lysine 909 acetylation in the presence of viral RNAs, promoting RIG-I sensing of viral RNAs. Depletion of HDAC6 expression led to impaired antiviral responses against RNA viruses, but not against DNA viruses. Consequently, HDAC6 knockout mice were highly susceptible to RNA virus infections compared to wild-type mice. These findings underscore the critical role of HDAC6 in the modulation of the RIG-I-mediated antiviral sensing pathway.