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

Abstract

Summary 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 (PegIFNα) 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 PegIFNα 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 PegIFNα in two CHB cohorts. Moreover, a polygenic score integrating TRIM26 rs116806878, STAT4 rs7574865 and CFB rs12614 (previously reported to be associated with response to PegIFNα) was related to response to PegIFNα 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 PegIFNα in patients with CHB.

Editorial: tripartite motif 26 inhibits hepatitis B virus replication and its genetic polymorphism predicts response to interferon treatment—towards a better understanding of interferon responsiveness in chronic hepatitis B. Authors' reply

“…7 Based on these findings, we elucidated the specific mechanism by how TRIM26 affects HBV replication and demonstrated in two cohorts (Cohort 1, n = 238, Cohort 2, n = 707) that TRIM26 rs116806878 is associated with pegylated interferonα treatment response in patients with HBeAg-positive CHB. 2 We agree with Dr Peng, and mentioned in the discussion section of our original article, that there are still some questions to be explored.…”

“…We thank Dr Peng for the insightful editorial 1 on our recently published paper. 2 In 2019, about 316 million people had chronic hepatitis B virus (HBV) infection globally. 3 However, HBV infection cannot be eradicated owing to the complexity of the HBV lifecycle.…”

“…Besides, TRIM26 can be induced by interferon‐β 7 . Based on these findings, we elucidated the specific mechanism by how TRIM26 affects HBV replication and demonstrated in two cohorts (Cohort 1, n = 238, Cohort 2, n = 707) that TRIM26 rs116806878 is associated with pegylated interferon‐α treatment response in patients with HBeAg‐positive CHB 2 …”

“…We thank Dr Peng for the insightful editorial 1 on our recently published paper 2 . In 2019, about 316 million people had chronic hepatitis B virus (HBV) infection globally 3 .…”

Editorial: tripartite motif 26 inhibits hepatitis B virus replication and its genetic polymorphism predicts response to interferon treatment—towards a better understanding of interferon responsiveness in chronic hepatitis B

“…Luo et al investigated the effect of TRIM26 on HBV replication and the underlying mechanism, and the association between single‐nucleotide polymorphisms (SNPs) in TRIM26 and PegIFNα treatment response in patients with HBeAg‐positive CHB 7 . They demonstrated that TRIM26 inhibited HBV replication by mediating HBx ubiquitination degradation through its SPRY domain and that interferon promoted TRIM26 expression in hepatocellular carcinoma cell lines.…”