FAT10 is phosphorylated by IKKβ to inhibit the antiviral type-I interferon response

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2023
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Life Science Alliance. Life Science Alliance. 2023, 7(1), e202101282. eISSN 2575-1077. Available under: doi: 10.26508/lsa.202101282
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IFN-I secretion provides a rapid host defense against infection with RNA viruses. Within the host cell, viral RNA triggers the activation of the RIG-I signaling pathway, leading to the production of IFN-I. Because an exaggerated IFN-I response causes severe tissue damage, RIG-I signaling is tightly regulated. One of the factors that control the IFN-I response is the ubiquitin-like modifier FAT10, which is induced by TNF and IFNγ and targets covalently FAT10-linked proteins for proteasomal degradation. However, the mechanism of how FAT10 modulates IFN-I secretion remains to be fully elucidated. Here, we provide strong evidence that FAT10 is phosphorylated by IκB kinase β (IKKβ) upon TNF stimulation and during influenza A virus infection on several serine and threonine residues. FAT10 phosphorylation increases the binding of FAT10 to the TRAF3-deubiquitylase OTUB1 and its FAT10-mediated activation. Consequently, FAT10 phosphorylation results in a low ubiquitylation state of TRAF3, which is unable to maintain interferon regulatory factor 3 phosphorylation and downstream induction of IFN-I. Taken together, we reveal a mechanism of how phosphorylation of FAT10 limits the production of tissue-destructive IFN-I in inflammation.

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570 Biowissenschaften, Biologie
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Cell Biology, Immunology, Microbiology, Virology, Host Pathogen Interaction
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ISO 690SAXENA, Kritika, Nicola D. ROVERATO, Melody REITHMANN, Mei Min MAH, Richard SCHREGLE, Gunter SCHMIDTKE, Ivan SILBERN, Henning URLAUB, Annette AICHEM, 2023. FAT10 is phosphorylated by IKKβ to inhibit the antiviral type-I interferon response. In: Life Science Alliance. Life Science Alliance. 2023, 7(1), e202101282. eISSN 2575-1077. Available under: doi: 10.26508/lsa.202101282
BibTex
@article{Saxena2023-11-08FAT10-68961,
  year={2023},
  doi={10.26508/lsa.202101282},
  title={FAT10 is phosphorylated by IKKβ to inhibit the antiviral type-I interferon response},
  number={1},
  volume={7},
  journal={Life Science Alliance},
  author={Saxena, Kritika and Roverato, Nicola D. and Reithmann, Melody and Mah, Mei Min and Schregle, Richard and Schmidtke, Gunter and Silbern, Ivan and Urlaub, Henning and Aichem, Annette},
  note={Article Number: e202101282}
}
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