Gadd45β is critical for regulation of type I interferon signaling by facilitating G3BP-mediated stress granule formation
W.A. Gayan Chathuranga,
Chamilani Nikapitiya,
Jae-Hoon Kim,
Kiramage Chathuranga,
Asela Weerawardhana,
Niranjan Dodantenna,
Doo-Jin Kim,
Haryoung Poo,
Jae U. Jung,
Chul-Ho Lee,
Jong-Soo Lee
Affiliations
W.A. Gayan Chathuranga
College of Veterinary Medicine, Chungnam National University, Daejeon 34314, Republic of Korea
Chamilani Nikapitiya
College of Veterinary Medicine, Chungnam National University, Daejeon 34314, Republic of Korea
Jae-Hoon Kim
College of Veterinary Medicine, Chungnam National University, Daejeon 34314, Republic of Korea; Livestock Products Analysis Division, Division of Animal Health, Daejeon Metropolitan City Institute of Health and Environment, Daejeon 34146, Republic of Korea
Kiramage Chathuranga
College of Veterinary Medicine, Chungnam National University, Daejeon 34314, Republic of Korea
Asela Weerawardhana
College of Veterinary Medicine, Chungnam National University, Daejeon 34314, Republic of Korea
Niranjan Dodantenna
College of Veterinary Medicine, Chungnam National University, Daejeon 34314, Republic of Korea
Doo-Jin Kim
Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
Haryoung Poo
Department of Biomedical Science and Engineering, Konkuk Institute of Technology, Konkuk University, Seoul 05029, Republic of Korea
Jae U. Jung
Department of Cancer Biology, Infection Biology Program, and Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Chul-Ho Lee
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRRIB), Daejeon 34141, Republic of Korea; Corresponding author
Jong-Soo Lee
College of Veterinary Medicine, Chungnam National University, Daejeon 34314, Republic of Korea; Corresponding author
Summary: Stress granules (SGs) constitute a signaling hub that plays a critical role in type I interferon responses. Here, we report that growth arrest and DNA damage-inducible beta (Gadd45β) act as a positive regulator of SG-mediated interferon signaling by targeting G3BP upon RNA virus infection. Gadd45β deficiency markedly impairs SG formation and SG-mediated activation of interferon signaling in vitro. Gadd45β knockout mice are highly susceptible to RNA virus infection, and their ability to produce interferon and cytokines is severely impaired. Specifically, Gadd45β interacts with the RNA-binding domain of G3BP, leading to conformational expansion of G3BP1 via dissolution of its autoinhibitory electrostatic intramolecular interaction. The acidic loop 1- and RNA-binding properties of Gadd45β markedly increase the conformational expansion and RNA-binding affinity of the G3BP1-Gadd45β complex, thereby promoting assembly of SGs. These findings suggest a role for Gadd45β as a component and critical regulator of G3BP1-mediated SG formation, which facilitates RLR-mediated interferon signaling.
