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


ABSTRACT: 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.

SUBMITTER: Saxena K 

PROVIDER: S-EPMC10631552 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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

Saxena Kritika K   Roverato Nicola Domenico ND   Reithmann Melody M   Mah Mei Min MM   Schregle Richard R   Schmidtke Gunter G   Silbern Ivan I   Urlaub Henning H   Aichem Annette A  

Life science alliance 20231108 1


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 degrad  ...[more]

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