TRIM26 inhibits hepatitis B virus replication by promoting HBx degradation and TRIM26 genetic polymorphism predicts PegIFNα treatment response of HBeAg-positive chronic hepatitis B Patients

作者：Luo, Mengqi; Hou, Jia; Mai, Haoming; Chen, Jiaxuan; Chen, Haitao; Zhou, Bin; Hou, Jinlin^*; Jiang, De-Ke^*

来源：Alimentary Pharmacology and Therapeutics, 2022, 56(5): 878-889.

DOI：10.1111/apt.17124

• X PROTEIN
• EFFICACY
• THERAPY
• BINDING
• SMC5/6
• STAT4

Background Hepatitis B virus (HBV) infection is a serious global health burden. TRIM26 has been reported to affect hepatitis C virus replication. Aims To manifest the role of TRIM26 on HBV replication and explore if there are single-nucleotide polymorphisms (SNPs) in TRIM26 associated with response to pegylated interferon-alpha (PegIFN alpha) treatment in patients with chronic hepatitis B (CHB). Methods We investigated the effect and mechanism of TRIM26 on HBV replication in vitro. The association between SNPs in TRIM26 and PegIFN alpha treatment response was evaluated in two independent cohorts including 238 and 707 patients with HBeAg-positive CHB. Results Knockdown of TRIM26 increased, while overexpression of TRIM26 inhibited, HBV replication. Co-immunoprecipitation assays and immunofluorescence showed that TRIM26 interacted and co-localised with HBx. Co-transfection of HBx-HIS and TRIM26-FLAG plasmids in Huh7 cells showed that TRIM26 inhibited the expression of HBx. Furthermore, TRIM26 inhibited HBV replication by mediating HBx ubiquitination degradation, and TRIM26 SPRY domain was responsible for the interaction and degradation of HBx. Besides, IFN increased TRIM26 expression. TRIM26 rs116806878 was associated with response to PegIFN alpha in two CHB cohorts. Moreover, a polygenic score integrating TRIM26 rs116806878, STAT4 rs7574865 and CFB rs12614 (previously reported to be associated with response to PegIFN alpha) was related to response to PegIFN alpha in CHB. Conclusions TRIM26 inhibits HBV replication; IFN promotes TRIM26 expression. TRIM26 exerts an inhibitory effect on HBx by promoting ubiquitin-mediated degradation of HBx. Furthermore, TRIM26 rs116806878 is a potential predictive biomarker of response to PegIFN alpha in patients with CHB.

• 单位
  南方医科大学; 中山大学