SERINC5 Inhibits the Secretion of Complete and Genome-Free Hepatitis B Virions Through Interfering With the Glycosylation of the HBV Envelope

Abstract

Serine incorporator 3 (SERINC3) and SERINC5 were recently identified as host intrinsic factors against human immunodeficiency virus (HIV)-1 and counteracted by HIV-1 Nef. However, whether they inhibit hepatitis B virus (HBV), which is a severe health problem worldwide, is unknown. Here, we demonstrate that SERINC5 potently inhibited HBV virion secretion in the supernatant without affecting intracellular core particle-associated DNA and the total RNA, but SERINC3 and SERINC1 did not. Further investigation discovered that SERINC5 increased the non-glycosylation of LHB, MHB, and SHB proteins of HBV and slightly decreased HBs proteins levels, which led to the decreased HBV secretion. Importantly, SERINC5 co-localized with LHB proteins in the Golgi apparatus, which is important for glycan processing and transport. In addition, we determined the functional domain in SERINC5 required for HBV inhibition, which was completely different from that required for HIV-1 restriction, whereas phosphorylation and glycosylation sites in SERINC5 were dispensable for HBV restriction. Taken together, our results demonstrate that SERINC5 suppresses HBV virion secretion through interfering with the glycosylation of HBV proteins, suggesting that SERINC5 might possess broad-spectrum antiviral activity.

ATP1B3 Restricts Hepatitis B Virus Replication Via Reducing the Expression of the Envelope Proteins

“…Detailed experimental procedures of HBV virions isolation were described in our previous report (Liu et al 2020 ). Briefly, HBV virions were immunoprecipitated from culture supernatant by anti-HBs antibody conjugated to protein G beads (#11243233001; Roche) overnight at 4 °C.…”

Regulation of Viral Restriction by Post-Translational Modifications

“…Indeed, only a recent study identified the residues N294 and N133 as glycosylated sites on SERINC5 (Figures 2 and 3B) [58]. However, even if N294 glycosylation seems to be important for its stability, a loss of glycosylation neither affects SERINC5 activity against HIV-1 nor HBV [58,113]. Future research may provide us with more answers regarding the regulation of these proteins by other PTMs.…”

“…Serine incorporators (SERINC) 3 and 5 have been identified as restriction factors against retroviruses [17,18,112] and against hepatitis B virus (HBV) [113]. Recently, the antiviral action of SERINC4 has also been established against HIV-1 [114].…”

“…In contrast to retroviruses, the mechanism of inhibition of HBV seems to be different. Indeed, SERINC5 interferes with the glycosylation of HBV-envelope protein, inhibiting in this way the complete production of HBV virions [113].…”

Challenges in the Application of Glyco-Technology to Hepatitis B Virus Therapy and Diagnosis

“…However, broad-spectrum glycosylation inhibitors could have a variety of side effects. It was recently reported that serine incorporator 5 (SERINC5) is a host intrinsic factor of an anti-human immunodeficiency virus (HIV) [ 29 ]. The functional domain of SERINC5 is essential for the inhibition of HBV secretion, but it is not required for inhibition of HIV-1 secretion.…”