Tu Wenhui, Liu Jin, Qian Feng, Zhu Li, Li Ming, Zheng Hui, Zhu Chuanwu
Department of Infectious Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Infectious Diseases, Taizhou Municipal Hospital, Taizhou, China.
J Med Virol. 2023 Mar;95(3):e28620. doi: 10.1002/jmv.28620.
Chronic hepatitis B (CHB) still cannot be cured currently, while the pursuit of a functional cure seems to be an accessible goal, in which the condition mainly depends on the serum hepatitis B surface antigen (HBsAg) levels. HBsAg may be downregulated by protein ubiquitination, which may facilitate finding a new potential intervention target for functional cure of CHB. We confirmed that β-transducin repeat-containing protein (β-TrCP) was the E3 ubiquitin ligase of HBsAg. β-TrCP specifically downregulated the expression of Myc-HBsAg. The degradation of Myc-HBsAg occurred via the proteasome pathway. Knockdown of β-TrCP increased Myc-HBsAg levels in HepG2 cells. The study further indicated that β-TrCP could affect the K48-linked polyubiquitin chain by acting on Myc-HBsAg. The GS G motif of HBsAg protein is required for β-TrCP-mediated degradation. Furthermore, we found that β-TrCP could significantly inhibit both intracellular and extracellular HBsAg levels produced by pHBV-1.3. Our study demonstrated that the E3 ubiquitin ligase β-TrCP induces K48-linked polyubiquitination of HBsAg, promotes the ubiquitination degradation of HBsAg, and downregulates intra- and extracellular HBsAg levels. Therefore, using the ubiquitination degradation pathway of HBsAg, it is possible to reduce HBsAg levels in CHB patients, which may be helpful in obtaining the goal of functional cure in the treatment of CHB patients.
慢性乙型肝炎（CHB）目前仍无法治愈，而追求功能性治愈似乎是一个可以实现的目标，其状况主要取决于血清乙型肝炎表面抗原（HBsAg）水平。HBsAg可能通过蛋白质泛素化而下调，这可能有助于找到慢性乙型肝炎功能性治愈的新潜在干预靶点。我们证实含β-转导素重复序列蛋白（β-TrCP）是HBsAg的E3泛素连接酶。β-TrCP特异性下调Myc-HBsAg的表达。Myc-HBsAg的降解通过蛋白酶体途径发生。敲低β-TrCP可增加HepG2细胞中Myc-HBsAg的水平。该研究进一步表明，β-TrCP可通过作用于Myc-HBsAg影响K48连接的多聚泛素链。HBsAg蛋白的GS G基序是β-TrCP介导降解所必需的。此外，我们发现β-TrCP可显著抑制pHBV-1.3产生的细胞内和细胞外HBsAg水平。我们的研究表明，E3泛素连接酶β-TrCP诱导HBsAg的K48连接多聚泛素化，促进HBsAg的泛素化降解，并下调细胞内和细胞外HBsAg水平。因此，利用HBsAg的泛素化降解途径，有可能降低慢性乙型肝炎患者的HBsAg水平，这可能有助于在慢性乙型肝炎患者的治疗中实现功能性治愈的目标。
