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

Xiaolian Cai; Rui Wang; Junji Zhu; Xiong Li; Xing Liu; Gang Ouyang; Jing Wang; Zhi Li; Chunchun Zhu; Hongyan Deng; Wuhan Xiao

doi:10.1016/j.celrep.2023.113606

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

Cell Rep. 2024 Jan 23;43(1):113606. doi: 10.1016/j.celrep.2023.113606. Epub 2023 Dec 20.

Authors

Xiaolian Cai¹, Rui Wang², Junji Zhu¹, Xiong Li³, Xing Liu³, Gang Ouyang¹, Jing Wang³, Zhi Li³, Chunchun Zhu¹, Hongyan Deng¹, Wuhan Xiao⁴

Affiliations

¹ Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, P.R. China.
² Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, P.R. China; College of Fisheries and Life Science, Dalian Ocean University, Dalian 116000, P.R. China.
³ Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China.
⁴ Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, P.R. China; Hubei Hongshan Laboratory, Wuhan 430070, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China. Electronic address: w-xiao@ihb.ac.cn.

PMID: 38127621
DOI: 10.1016/j.celrep.2023.113606

Abstract

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.

Keywords: CP: Immunology; FIH; IKKϵ; MAVS; TBK1; TRAF3; hydroxylation; hypoxia; innate immunity; mouse; zebrafish.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Hydroxylation
I-kappa B Kinase* / metabolism
Immunity, Innate
Mice
Repressor Proteins / metabolism
Virus Diseases*
Zebrafish / metabolism

Substances

I-kappa B Kinase
Repressor Proteins