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. 2025 Oct;32(10):1806-1819.
doi: 10.1038/s41418-025-01491-x. Epub 2025 Mar 28.

The USP43/RNF2 axis negatively regulates antiviral innate immunity by promoting TBK1 ubiquitination and degradation

Xibao Zhao #  1 , Qianqian Di #  1 , Jin Chen  1 , Jing Ling  2 , Jiazheng Quan  1 , Zizhao Zhao  2 , Hongrui Li  2 , Shaoying Chen  1 , Xunwei Li  1 , Xiwei Guo  1 , Han Wu  1 , Yue Xiao  1 , Weilin Chen  3   4
Affiliations

The USP43/RNF2 axis negatively regulates antiviral innate immunity by promoting TBK1 ubiquitination and degradation

Xibao Zhao et al. Cell Death Differ. 2025 Oct.

Abstract

The E3 ubiquitin ligase usually regulates the substrate proteins ubiquitination and degradation, but the study of itself post-translational modification and stability is still elusive. Here, we reveal that E3 ubiquitin ligase ring finger protein 2 (RNF2) is deubiquitinated and stabilized by ubiquitin specific peptidase 43 (USP43) through interactome and quantitative ubiquitinome mass spectrometry analysis. This study demonstrated that USP43, as a deubiquitinating enzyme, negatively regulates the expression of type I interferon (IFN) and the Usp43 deficient enhances antiviral innate immune response against VSV infection both in vitro and in vivo. Mechanistically, USP43 negatively regulates antiviral immunity by promoting RNF2-mediated TBK1 ubiquitination and degradation. USP43 stabilizes RNF2 by removing K48-linked ubiquitination of RNF2 at Lys239 and Lys249, while RNF2 promotes TBK1 degradation by increasing K48-linked ubiquitination of TBK1 at Lys670. These findings uncover the E3 ubiquitin ligase RNF2 post-translational ubiquitination modification and stability regulation, and reveals a novel mechanism that the USP43/RNF2 axis in regulating antiviral innate immunity.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethical approval: The studies did not involve human participants, human data or human tissue. All animal experiments were accomplished in compliance with ethical standards, and approved by the Animal Care Committee of Shenzhen University (Shenzhen, China), and performed in accordance with the “China Guide for the Protection and Use of Laboratory Animals”.

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