Abstract
Hepatitis B virus (HBV) belongs to the Hepadnaviridae family of enveloped DNA viruses. Recent studies have found that host factors can suppress HBV replication. HBV envelope proteins are reported to be degraded by the endoplasmic reticulum-associated degradation (ERAD) pathway. As a component of the ERAD pathway, suppressor of lin-12-like 1 (SEL1L) was earlier found to be upregulated in the inactive carrier phase of chronic HBV infection relative to that in the immune tolerant phase. However, the role of SEL1L in regulating HBV replication remains largely unknown. In this study, we found the levels of HBV RNA, DNA, and core and envelope proteins to be significantly downregulated by SEL1L overexpression and upregulated by SEL1L silencing in Huh7 cells transiently transfected with an overlength HBV genome. Similar upregulation was observed in HepG2.2.15 cells as well. SEL1L co-localized with HBV surface antigen (HBsAg), which changed its staining pattern. Treatment with an inhibitor of ERAD pathway remarkably increased intracellular S protein. Surprisingly, silencing SEL1L to block the ERAD pathway activated an alternative ER quality control (ERQC)-autophagy pathway, which might account for the increased HBV RNAs and core protein. Together, our results demonstrate that SEL1L is a host restriction factor that exerts anti-HBV effect through ERAD and alternative ERQC-autophagy pathway.
Highlights
Hepatitis B virus (HBV) infection is a common public health concern worldwide (Schweitzer et al, 2015)
Our present study raised the possibility of suppressor of lin-12-like 1 (SEL1L) playing an indispensable role in either endoplasmic reticulum-associated degradation (ERAD) or endoplasmic reticulum (ER) quality control (ERQC)-autophagy pathway to degrade viral proteins and inhibit HBV replication
We noticed that SEL1L did not inhibit HBV promoters, which suggested post-transcriptional mechanisms to be involved in the reduction of HBV RNA and core proteins
Summary
The immune tolerant (IT) and inactive carrier (IC) phases of CHB are considered to maintain a similar inactivated host immune status, they have entirely different virological characteristics. SEL1L protein is a core component of an endoplasmic reticulum (ER) quality control pathway, namely the endoplasmic reticulum-associated degradation (ERAD) pathway, which in turn plays a vital role in preserving a secretory function by recognizing terminally misfolded polypeptides and processing them for proteasomal degradation (Vembar and Brodsky, 2008). A previous report had found HBV to activate the ERAD pathway by increased expression of ER degradation-enhancing mannosidaselike proteins (EDEMs), leading to reduced amount of intracellular envelope proteins (Lazar et al, 2012). Whether SEL1L, a vital component of ERAD pathway, can regulate HBV life cycle, still remains unknown. We demonstrated that SEL1L functioned as a host restriction factor against HBV replication. Silencing SEL1L could activate ER quality control (ERQC)autophagy pathway, which was considered as an alternative route for protein degradation
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