Ubiquitin E3 ligase β‐TrCP negatively regulates surface protein of hepatitis B virus

Abstract

AbstractChronic 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 GS137G 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.