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J. Med. Virol., Mar 2024, 96 (3) | https://doi.org/10.1002/jmv.29523
SIAH1 modulates antiviral immune responses by targeting deubiquitinase USP19
Asela Weerawardhana 1, Thilina U. B. Herath 1, W A Gayan Chathuranga 1, Tae-Hwan Kim 1, Pathum Ekanayaka 1, Kiramage Chathuranga 1, Ho-Chul Kang 2, Jae U Jung 3, Jong-Soo Lee 1
1College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea.
2Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.
3Department of Cancer Biology, Infection Biology Program, and Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Asela Weerawardhana and Thilina U.B. Herath are contributed equally to this study.
CORRESPONDING AUTHOR : Jong-Soo Lee
Abstract
Tight control of the type I interferon (IFN) signaling pathway is critical for maintaining host innate immune responses, and the ubiquitination and deubiquitination of signaling molecules are essential for signal transduction. Deubiquitinase ubiquitin-specific protein 19 (USP19) is known to be involved in deubiquitinating Beclin1, TRAF3, and TRIF for downregulation of the type I IFN signaling. Here, we show that SIAH1, a cellular E3 ubiquitin ligase that is involved in multicellular pathway, is a potent positive regulator of virus-mediated type I IFN signaling that maintains homeostasis within the antiviral immune response by targeting USP19. In the early stages of virus infection, stabilized SIAH1 directly interacts with the USP19 and simultaneously mediates K27-linked ubiquitination of 489, 490, and 610 residues of USP19 for proteasomal degradation. Additionally, we found that USP19 specifically interacts with MAVS and deubiquitinates K63-linked ubiquitinated MAVS for negative regulation of type I IFN signaling. Ultimately, we identified that SIAH1-mediated degradation of USP19 reversed USP19-mediated deubiquitination of MAVS, Beclin1, TRAF3, and TRIF, resulting in the activation of antiviral immune responses. Taken together, these findings provide new insights into the molecular mechanism of USP19 and SIAH1, and suggest a critical role of SIAH1 in antiviral immune response and homeostasis.
논문정보
- Research article
- 2024년 03월 (BRIC 등록일 2024-03-19)
- 국내(교신)+국외 연구진
- 의약학 > 분자세포의학
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