SIAH1 modulates antiviral immune responses by targeting deubiquitinase USP19

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 invol...

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Bibliographic Details
Published in:Journal of medical virology 2024-03, Vol.96 (3), p.e29523-n/a
Main Authors: Weerawardhana, Asela, Herath, Thilina U. B., Gayan Chathuranga, W. A., Kim, Tae‐Hwan, Ekanayaka, Pathum, Chathuranga, Kiramage, Kang, Ho‐Chul, Jung, Jae U., Lee, Jong‐Soo
Format: Article
Language:English
Subjects:
Adaptor Proteins, Vesicular Transport
antiviral
Beclin-1
Degradation
Deubiquitinating Enzymes - genetics
Deubiquitinating Enzymes - metabolism
deubiquitination
Endopeptidases - genetics
Endopeptidases - metabolism
Homeostasis
Humans
Immune response
Immune system
Immunity, Innate
Innate immunity
Interferon
Interferon Type I - metabolism
MAVS
Molecular modelling
Proteasomes
SIAH1
Signal transduction
TNF Receptor-Associated Factor 3 - genetics
Ubiquitin - metabolism
Ubiquitin-protein ligase
Ubiquitination
USP19
Viruses
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Summary: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.
ISSN:0146-6615
1096-9071
DOI:10.1002/jmv.29523