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- Title
UBE2O reduces the effectiveness of interferon-α via degradation of IFIT3 in hepatocellular carcinoma.
- Authors
Li, Heng; Liu, Yao; Cheng, Can; Wu, Yang; Liang, Shu-Hang; Wu, Liang; Wang, Hong; Tu, Cong-yin; Yao, Han-Hui; Meng, Fan-Zheng; Zhang, Bo; Wang, Wei; Wang, Jia-Bei; Liu, Lian-Xin
- Abstract
Interferon (IFN) exerts its effects through interferon-stimulated genes (ISGs), but its efficacy is limited by interferon resistance, which can be caused by the ubiquitination of key proteins. UBE2O was initially identified as a promising therapeutic target based on data from the TCGA and iUUCD 2.0 databases. Through the inhibition of UBE2O, interferon α/β signaling and overall interferon signaling were activated. Integrating data from proteomic, mass spectrometry, and survival analyses led to the identification of IFIT3, a mediator of interferon signaling, as a ubiquitination substrate of UBE2O. The results of in vitro and in vivo experiments demonstrated that the knockdown of UBE2O can enhance the efficacy of interferon-α by upregulating IFIT3 expression. K236 was identified as a ubiquitination site in IFIT3, and the results of rescue experiments confirmed that the effect of UBE2O on interferon-α sensitivity is dependent on IFIT3 activity. ATO treatment inhibited UBE2O and increased IFIT3 expression, thereby increasing the effectiveness of interferon-α. In conclusion, these findings suggest that UBE2O worsens the therapeutic effect of interferon-α by targeting IFIT3 for ubiquitination and degradation.
- Publication
Cell Death & Disease, 2023, Vol 14, Issue 12, p1
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-023-06369-9