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Envelope Proteins of Hepatitis B Virus: Molecular Biology and Involvement in Carcinogenesis

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viruses Review Envelope Proteins of Hepatitis B Virus: Molecular Biology and Involvement in Carcinogenesis Jun Inoue * , Kosuke Sato, Masashi Ninomiya and Atsushi Masamune Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; [email protected] (K.S.); [email protected] (M.N.); [email protected] (A.M.) * Correspondence: [email protected]; Tel./Fax: +81-22-717-7171 Abstract: The envelope of hepatitis B virus (HBV), which is required for the entry to hepatocytes, consists of a lipid bilayer derived from hepatocyte and HBV envelope proteins, large/middle/small hepatitis B surface antigen (L/M/SHBs). The mechanisms and host factors for the envelope formation in the hepatocytes are being revealed. HBV-infected hepatocytes release a large amount of subviral particles (SVPs) containing L/M/SHBs that facilitate escape from the immune system. Recently, novel drugs inhibiting the functions of the viral envelope and those inhibiting the release of SVPs have been reported. LHBs that accumulate in ER is considered to promote carcinogenesis and, especially, deletion mutants in the preS1/S2 domain have been reported to be associated with the development of hepatocellular carcinoma (HCC). In this review, we summarize recent reports on the findings regarding the biological characteristics of HBV envelope proteins, their involvement in HCC development and new agents targeting the envelope. Keywords: HBV; envelope; Dane particle; subviral particle Citation: Inoue, J.; Sato, K.; Ninomiya, M.; Masamune, A. Envelope Proteins of Hepatitis B Virus: Molecular Biology and 1. Introduction Involvement in Carcinogenesis. Hepatitis B virus (HBV) infects 292 million people chronically in the world despite the Viruses 2021, 13, 1124. https:// availability of an effective vaccine [1], and they are at risk of liver cirrhosis and hepatocel- doi.org/10.3390/v13061124 lular carcinoma (HCC) [2]. Although antiviral therapies such as nucleos(t)ide analogues (NAs) and interferon have been developed, complete eradication of HBV is still difficult Academic Editor: Philippe Gallay because covalently closed circular DNA (cccDNA), which is a highly stable and active epi- somal genome, is formed in the nucleus of HBV-infected hepatocytes [3]. Even if patients Received: 26 May 2021 have received NA therapy and HBV replication is inhibited, they still have the potential to Accepted: 9 June 2021 Published: 11 June 2021 develop liver cancer [4,5]. Therefore, novel antiviral therapies are required clinically and several lines of clinical trials for HBV chronic infection are ongoing [6,7]. Publisher’s Note: MDPI stays neutral The mature infectious HBV particle with a diameter of 42 nm, which is also called with regard to jurisdictional claims in a “Dane particle”, consists of an envelope and nucleocapsid containing HBV DNA and published maps and institutional affil- polymerase (Figure1). A large amount of hepatitis B surface antigen (HBsAg) subviral iations. particles (SVPs), which do not include nucleocapsid, is released from HBV-infected hepato- cytes [8] and HBsAg assays detect both Dane particles and SVPs. Additionally, the infected hepatocytes release several kinds of other immature particles [9]. Hepatitis B e antigen (HBeAg) is also secreted from the infected hepatocytes and is detected in the serum of patients. HBeAg seroconversion, defined as loss of HBeAg and appearance of anti-HBe Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. antibody, occurs both in the natural course and under treatment. HBeAg-defective pre- This article is an open access article core mutants are found in most inactive HBV carriers with undetectable HBeAg [10,11]. distributed under the terms and SVPs and HBeAg are not essential for the infection, but they are considered to help the conditions of the Creative Commons establishment of persistent infection of HBV via effects on the immune system [8]. The Attribution (CC BY) license (https:// HBV envelope, which is considered to be essential for the infection [12], is composed of creativecommons.org/licenses/by/ a cellular lipid bilayer and three HBV surface proteins: large/middle/small hepatitis B 4.0/). surface proteins (LHBs/MHBs/SHBs). The ratio of LHBs, MHBs and SHBs in the envelope Viruses 2021, 13, 1124. https://doi.org/10.3390/v13061124 https://www.mdpi.com/journal/viruses Viruses 2021, 13, x FOR PEER REVIEW 2 of 11 Viruses 2021, 13, 1124 2 of 11 cellular lipid bilayer and three HBV surface proteins: large/middle/small hepatitis B sur- face proteins (LHBs/MHBs/SHBs). The ratio of LHBs, MHBs and SHBs in the envelope of of Dane particles was reported to be approximately 1:1:4 [13]. Moreover, hepatitis D virus Dane particles was reported to be approximately 1:1:4 [13]. Moreover, hepatitis D virus (HDV) requires the HBV envelope for the packaging. Therefore, the HBV envelope is (HDV) requires the HBV envelope for the packaging. Therefore, the HBV envelope is in- indispensable for the life cycle of HBV and HDV and could be an antiviral target against dispensable for the life cycle of HBV and HDV and could be an antiviral target against these viruses that are tough to beat. these viruses that are tough to beat. FigureFigure 1. 1. SchemaSchema of of HBV HBV-associated-associated particles. particles. Dane Dane particles particles are 42 are nm 42 in nm diameter in diameter,, and their and enve- their lope consists of large/middle/small hepatitis B surface proteins (LHBs/MHBs/SHBs) and a nucle- envelope consists of large/middle/small hepatitis B surface proteins (LHBs/MHBs/SHBs) and ocapsid containing viral genome and polymerase. There are 2 forms of subviral particles, filament aand nucleocapsid sphere. The containing former consists viral genome of LHBs, and MHBs polymerase. and SHBs, There and arethe 2latter forms consists of subviral of MHBs particles, and filamentSHBs. and sphere. The former consists of LHBs, MHBs and SHBs, and the latter consists of MHBs and SHBs. As for the carcinogenesis of HBV, hepatitis B x protein (HBx) and LHBs are consid- eredAs to for play the major carcinogenesis roles in the of HBV,infected hepatitis hepatocytes. B x protein HBx (HBx) is included and LHBs often are in considered the HBV toDNA play that major is integrated roles in the into infected the host hepatocytes. DNA of HCC HBx tissue is included and has often been inreported the HBV to DNAhave thatmultifunctional is integrated roles into thein the host modulation DNA of HCC of the tissue expression/activities and has been reported of many to havegenes multi- [14]. functionalLHBs accumulation roles in the in modulation the endoplasmic of the reticulum expression/activities (ER) has been of documented many genes to [14 associate]. LHBs accumulationwith ER stress in responses, the endoplasmic which lead reticulum to pro-oncogenic (ER) has been effects documented [15]. In this toreview, associate we sum- with ERmarize stress the responses, biological which characteristics lead to pro-oncogenic of HBV envelope effects and [15 ].SVPs In this and review, the roles we of summarize envelope theproteins biological in the characteristics hepatocarcinogenesis. of HBV envelope and SVPs and the roles of envelope proteins in the hepatocarcinogenesis. 2. Biological Characteristics of HBV Envelope 2. Biological Characteristics of HBV Envelope The HBV envelope proteins, LHBs, MHBs and SHBs, are translated from 2.4/2.1 kb The HBV envelope proteins, LHBs, MHBs and SHBs, are translated from 2.4/2.1 kb mRNAs, which are transcribed from cccDNA. Additionally, these mRNAs are transcribed mRNAs, which are transcribed from cccDNA. Additionally, these mRNAs are transcribed from integrated viral genome. The C-terminus of LHBs, MHBs and SHBs is common, and from integrated viral genome. The C-terminus of LHBs, MHBs and SHBs is common, the length is 400 (389), 281 and 226 amino acids, respectively (Figure 2A). The LHBs con- and the length is 400 (389), 281 and 226 amino acids, respectively (Figure2A). The LHBs sists of preS1, preS2 and S domains, and MHBs consists of preS2 and S domains. There consists of preS1, preS2 and S domains, and MHBs consists of preS2 and S domains. are 4 transmembrane domains in SHBs and “a” determinant that is exposed on the outside There are 4 transmembrane domains in SHBs and “a” determinant that is exposed on of the envelope (Figure 2B). The “a” determinant is an antigenic domain that is a major the outside of the envelope (Figure2B). The “a” determinant is an antigenic domain target of neutralizing antibodies [16]. The N-terminus is myristoylated at glycine 2, which that is a major target of neutralizing antibodies [16]. The N-terminus is myristoylated at is considered to be essential for the infection [17]. Myristoylation is a posttranslational glycine 2, which is considered to be essential for the infection [17]. Myristoylation is a modification and myristic acid is attached by the ubiquitous enzyme N-myristoyltrans- posttranslational modification and myristic acid is attached by the ubiquitous enzyme ferase (NMT). Because the myristic acid is a hydrophobic moiety, the myristoylated part N-myristoyltransferase (NMT). Because the myristic acid is a hydrophobic moiety, the is inserted into hydrophobic regions in the lipid bilayer [18]. Using the myristic acid as an myristoylated part is inserted into hydrophobic regions in the lipid bilayer [18]. Using anchor, the preS1 and preS2 in LHBs are considered to be able to transit between the cy- the
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