Hepatitis B subviral envelope particles use the COPII machinery for intracellular transport via selective exploitation of Sec24A and Sec23B

Abstract

Hepatitis B virus (HBV) is a leading cause of liver disease. Its success as a human pathogen is related to the immense production of subviral envelope particles (SVPs) contributing to viral persistence by interfering with immune functions. To explore cellular pathways involved in SVP formation and egress, we investigated hostpathogen interactions. Yeast-based proteomics revealed Sec24A, a component of the coat protein complex II (COPII), as an interaction partner of the HBV envelope S domain. To understand how HBV co-opts COPII as a proviral machinery, we studied roles of key Sec proteins in HBV-expressing liver cells. Silencing of Sar1, Sec23, and Sec24, which promote COPII assembly concomitant with cargo loading, strongly diminished endoplasmic reticulum (ER) envelope export and SVP secretion. By analysing Sec paralog specificities, we unexpectedly found that the HBV envelope is a selective interaction partner of Sec24A and Sec23B whose functions could not be substituted by their related isoforms. In support, we found that HBV replication upregulated Sec24A and Sec23B transcription. Furthermore, HBV encountered the Sec24A/Sec23B complex via an interaction that involved the N-terminal half of Sec24A and a di-arginine motif of its S domain, mirroring a novel ER export code.Accordingly, an interference with the COPII/HBV cross-talk might display a tool to effectively inhibit SVP release.

Interplay between Cellular Autophagy and Hepatitis B Virus Replication: A Systematic Review

“…An increasing number of studies have reported that the ER-derived COPII-coated vesicles, which bud at the ER exit site (ERES), are redirected away from the Golgi and toward the nascent phagophore, thereby contributing to autophagosome formation in both yeast and mammalian cells [54][55][56]. A recent study by Zeyen et al has found that the HBV envelope selectively encounters the SEC24A/SEC23B complex in COPII vesicles through a direct interaction involving the N-terminal of SEC24A and a di-arginine motif of its S domain, indicating that viral envelope coating in COPII vesicles serves an important source of autophagy mediated-HBV envelope formation [57]. Therefore, autophagosomes and other autophagic compartments provide a physical scaffold for HBV envelopment and serve as a source of viral envelope membranes.…”

Hepatitis B Virus Exploits ERGIC-53 in Conjunction with COPII to Exit Cells

“…These particles, also referred to as hepatitis B surface antigen (HBsAg) particles, are secreted in extreme surplus compared to the infectious HBV particles and are thought to act as decoys to the immune system [26,27]. The viral S envelope protein alone is sufficient for the production of spherical SVPs with diameters of about 22 nm that are formed by self-assembly of about 100 S molecules in the ER-Golgi intermediate compartment (ERGIC) and are released via the constitutive pathway of secretion [28,29]. Remarkably, the budding and secretion of spherical SVPs does neither require N146-linked glycans [11,13,14] nor ESCRTs [21,23], implicating that HBV exploits distinct cellular pathways and host factors to release its particle types.…”

“…In the search for host factors involved in HBV particle-type exports, we recently employed yeast-based proteomics and identified Sec24A as an interaction partner of the HBV envelope S domain [29]. Sec24 is the cargo adaptor of the coat protein complex II (COPII), a vesicular transport machinery that moves selected secretory cargos from the ER to the Golgi apparatus.…”

“…Mapping analyses additionally showed that the Sec24A isoform binds to a di-arginine motif of the HBV S domain, a novel ER export code, in a productive manner. A blockage of the COPII/HBV crosstalk, created by interference with this binding motif, inhibited the ER exit of S and, thus, the secretion of the spherical SVPs [29].…”

Modification of the Mammalian Endomembrane System in Healthy and Diseased Cells

“…This organelle occupies a significant volume in many cell types, and, as such, is a natural target for exploitation by viruses that need a source of membranes for their assembly in infected cells. Indeed, recent articles have highlighted that not only is it the ER membrane that is used by viruses, but that, in fact, certain viruses such as hepatitis B [17] and rotavirus [18] specifically subvert the ER export machinery, as discussed in [3], to their ends. Arakawa and Morita provide a detailed review of how the ER is used as a replication organelle for the flaviviruses, a group that includes the dengue, Zika and tick-borne encephalitis viruses, among others [5].…”