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Deubiquitinase-dependent transcriptional silencing controls inflammation

Yuxin Yi^1,2,3 , Wenjie Xu^1,2,3 , Pengcheng Mi^1,2,3 , Siliang Ye^1,2,3 , Li Chen³ , Neal M. Alto⁴ , Zixu Liu^1,2,3,5,6,*

¹School of Medicine, Westlake University, Hangzhou, Zhejiang, China
²Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, Westlake University, Hangzhou, Zhejiang, China
³School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
⁴Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
⁵Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
⁶Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China
* Correspondence: Zixu Liu(liuzixu@westlake.edu.cn)

Transcriptional control is crucial for the regulation of inflammation. While it is well-established that inducible transcriptional repressors are synthesized de novo through signal-dependent transcriptional upregulation, it remains unclear whether post-translational modification mechanisms, such as deubiquitination, also contribute to this process. We previously identified developmentally silenced sine oculis (SIX) transcription factors that are reactivated to control inflammatory gene transcription in differentiated immune cells under chronic microbial infections. However, the molecular mechanisms by which this transcriptional silencing process is regulated remain unclear. Here, we report that USP2, a deubiquitinase localized in the nucleus and induced by inflammatory signals, stabilizes SIX proteins through deubiquitination under inflammatory conditions. Consequently, the USP2-SIX complex acts in concert to control NF-κB-mediated inflammatory gene transcription by directly targeting gene promoters. Supporting this mechanism, Usp2^−/− mice exhibit higher mortality during H1N1 infections, which phenocopies Six1^−/− mice, attributed to elevated levels of life-threatening inflammatory mediators and exacerbated pathology. This study establishes a deubiquitinase-dependent transcriptional control of the inflammatory response to prevent immunopathology, offering new therapeutic avenues for combating infectious diseases.

https://doi.org/10.1038/s41422-025-01140-5

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