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Rise above the stress—Endoplasmic reticulum stress and autophagy enhance the release of hepatitis B virus subparticles

All viruses are masters of subverting and manipulating host biological pathways to complete their life cycles, which generally are composed of viral entry, genome duplication, viral assembly, and egress. One virus that is especially well adapted to exploit its host's resources is HBV. With a genome of about 3 kb, HBV is one of the smallest pathogenic viruses and naturally infects only humans and chimpanzees.[1] Half a century after HBV was identified as the etiological agent of a devastating serummediated hepatitis disease, many secrets about the HBV life cycle remain uncovered, including how it is released from cells. HBV is a peculiar virus that leads to secretion of not only mature infectious virions from infected cells but also a myriad of subparticles, including subviral particles (SVPs) and empty capsids. The release of these particles is a complex process that requires intricate interaction and interplay between the host and viral factors.[2– 4] Although there is still much left to uncover, research over the past 10 years has provided great insights into the considerable complexity of this process (Figure 1). Mature virions are mainly sorted through the endosomal sorting complex required for transport (ESCRT) into late endosomes, or multivesicular bodies (MVBs), which can fuse with the plasma membrane to release their cargo.[2] This ESCRT– MVB release pathway involves ESCRTs 0, I, II, and III and the vacuolar protein sorting 4 ATPase, as well as other associated factors (Figure 1). Ubiquitin appears to be important for cargo sorting because ESCRTs 0, I, and II are known to harbor ubiquitinbinding domains. It has been proposed that the clathrin adaptor protein family member γ2adaptin serves as a scaffold protein that forms a preassembly complex composed of large HBsAg (LHBs), HBV capsid, and ubiquitylated ubiquitin E3 ligase neural precursor cell expressed developmentally downregulated protein 4 (Nedd4) (Figure 1).[2] The complex subsequently engages ubiquitin binding ESCRT components and initiates the sorting and packaging process in MVBs. In addition, a host factor, αtaxilin, has been implicated in bridging the interaction of LHBs and the ESCRT machinery to initiate ESCRT– MVBmediated release (Figure 1).[3,5] Cells infected with HBV secrete two major types of HBV SVPs: spherical and filamentous. These SVPs are similar to infectious Dane particles, comprised of HBsAgs embedded in a hostderived lipid bilayer, but are devoid of the HBV genome. The spherical SVPs mainly contain the small surface antigen (SHBs), while the filamentous SVPs contain all three small surface antigens (SHBs), medium surface antigens, and LHBs. Transport and release of these two types of HBV also vary considerably. The spherical SVPs are transported through the endoplasmic reticulum (ER)– Golgi intermediate compartment (ERGIC) and released by the general secretory pathway, whereas the release of the filamentous SVPs has been proposed to resemble that of the mature virions and requires the ESCRT– MVB pathway, presumably due to the different composition of envelope proteins (Figure 1).[2– 4] In contrast to both types of SVPs, the secretion of HBV empty capsids is accomplished through a nonvesicular exocytosis process (Figure 1). Two cellular factors, hepatocyte growth factor– regulated tyrosine kinase substrate (HGS), which is a component of the ESCRT0 complex, and apoptosislinked gene 2 interacting protein (Alix), are thought to be involved; but the detailed mechanism of release remains to be elucidated (Figure 1).[2,3] However, apparently the story does not end here; and more pathways, such as ER stress and autophagy, emerge as potential players involved in the release of these HBV particles. ER stress is a broad phenomenon mainly caused by calcium or redox imbalance that leads to accumulation of misfolded proteins due to defective protein glycosylation or folding defects. ER stress also elicits expansive cellular responses including the unfolded protein response (UPR), which is initiated and regulated through three ERresident sensors, namely doublestranded RNAactivated protein kinase– like ER kinase (PERK), transcription factor 6 (ATF6), and inositolrequiring enzyme 1 (IRE1). All of these proteins may participate in crosstalk with autophagy, which normally leads to formation of an autophagosome that is Received: 6 December 2021 | Accepted: 6 December 2021