Factor inhibiting HIF negatively regulates antiviral innate immunity via hydroxylation of IKKϵ

Activation of type I interferon (IFN-1) signaling is essential to protect host cells from viral infection. The full spectrum of IFN-I induction requires the activation of a number of cellular factors, including IκB kinase epsilon (IKKϵ). However, the regulation of IKKϵ activation in response to vira...

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Published in:Cell reports (Cambridge) 2024-01, Vol.43 (1), p.113606-113606, Article 113606
Main Authors: Cai, Xiaolian, Wang, Rui, Zhu, Junji, Li, Xiong, Liu, Xing, Ouyang, Gang, Wang, Jing, Li, Zhi, Zhu, Chunchun, Deng, Hongyan, Xiao, Wuhan
Format: Article
Language:English
Subjects:
CP: Immunology
FIH
hydroxylation
hypoxia
IKKϵ
innate immunity
MAVS
mouse
TBK1
TRAF3
zebrafish
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Summary:Activation of type I interferon (IFN-1) signaling is essential to protect host cells from viral infection. The full spectrum of IFN-I induction requires the activation of a number of cellular factors, including IκB kinase epsilon (IKKϵ). However, the regulation of IKKϵ activation in response to viral infection remains largely unknown. Here, we show that factor inhibiting hypoxia-inducible factor (HIF) (FIH), an asparaginyl hydroxylase, interacts with IKKϵ and catalyzes asparagine hydroxylation of IKKϵ at Asn-254, Asn-700, and Asn-701, resulting in the suppression of IKKϵ activation. FIH-mediated hydroxylation of IKKϵ prevents IKKϵ binding to TBK1 and TRAF3 and attenuates the cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex-catalyzed K63-linked polyubiquitination of IKKϵ at Lys-416. In addition, Fih-deficient mice and zebrafish are more resistant to viral infection. This work uncovers a previously unrecognized role of FIH in suppressing IKKϵ activation for IFN signaling and antiviral immune responses. [Display omitted] •FIH catalyzes the asparagine hydroxylation of IKKϵ at Asn-254, Asn-700, and Asn-701•FIH suppresses IKKϵ activation•FIH-mediated hydroxylation of IKKϵ prevents IKKϵ binding to TBK1 and TRAF3•FIH attenuates K63-linked polyubiquitination of IKKϵ at Lys-416 Cai et al. demonstrate that FIH catalyzes asparagine hydroxylation of IKKϵ at Asn-254, Asn-700, and Asn-701, resulting in the prevention of IKKϵ binding to TBK1 and TRAF3. As a result, FIH attenuates K63-linked polyubiquitination of IKKϵ at Lys-416, thereby suppressing IKKϵ activation and negatively regulating antiviral immunity.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2023.113606