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      • Record: found
      • Abstract: found
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      Hepatitis B Virus Utilizes a Retrograde Trafficking Route via the Trans-Golgi Network to Avoid Lysosomal Degradation

      research-article
      Author(s): 1 , ∗ , 1 , 1 , 2 , 1 , 2 , 1 , 1 , 1 , 1 , 1 , 1 , 2 , 1 , 1 , 3 , 3 , 4 , 5 , 6 , 6 , 5 , 1 , 4 , 1 , 1 , 1 , 2 , ∗ , ∗
      Publication date (Electronic):
      Journal: Cellular and Molecular Gastroenterology and Hepatology
      Publisher: Elsevier
      Keywords: cccDNA, DOCK11, Retrograde Trafficking, AGAP2, AGAP2, Arf-GAP with GTPase, ankyrin repeat, and pleckstrin homology domain-containing protein 2 , ARF1, ADP ribosylation factor 1, BFA, brefeldin A, cccDNA, covalently closed circular viral DNA, CDC42, cell division cycle 42, CHB, chronic hepatitis B, COPI, coat protein I, DHR2, DOCK homology region 2, DOCK11, dedicator of cytokinesis 11, Dox, doxycycline, EE, early endosome, ER, endoplasmic reticulum, ETV, entecavir, GEF, guanine nucleotide exchange factor, GEq, genome equivalents, GFP, green fluorescent protein, HBcAg, HBV core antigen, HBcrAg, HBV core-related antigen, HBsAg, HBV surface antigen, HBV, hepatitis B virus, HCC, hepatocellular carcinoma, Ig, immunoglobulin, LE, late endosome, Luc, luciferase, NL, NanoLuc, NTCP, Na/taurocholate cotransporting polypeptide, PBS, phosphate-buffered saline, PCR, polymerase chain reaction, PXB cells, primary human hepatocytes, PLA, proximity ligation assay, RAB7KO, Rab7 knockout, RTD, real-time detection, shDOCK11, DOCK11 short hairpin RNA, shRNA, short hairpin RNA, siRNA, small interfering RNA, STX, Shiga toxin, TGN, trans-Golgi network

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          Abstract

          Background & Aims

          Hepatitis B virus (HBV) infection is difficult to cure owing to the persistence of covalently closed circular viral DNA (cccDNA). We performed single-cell transcriptome analysis of newly established HBV-positive and HBV-negative hepatocellular carcinoma cell lines and found that dedicator of cytokinesis 11 (DOCK11) was crucially involved in HBV persistence. However, the roles of DOCK11 in the HBV lifecycle have not been clarified.

          Methods

          The cccDNA levels were measured by Southern blotting and real-time detection polymerase chain reaction in various hepatocytes including PXB cells by using an HBV-infected model. The retrograde trafficking route of HBV capsid was investigated by super-resolution microscopy, proximity ligation assay, and time-lapse analysis. The downstream molecules of DOCK11 and underlying mechanism were examined by liquid chromatography-tandem mass spectrometry, immunoblotting, and enzyme-linked immunosorbent assay.

          Results

          The cccDNA levels were strongly increased by DOCK11 overexpression and repressed by DOCK11 suppression. Interestingly, DOCK11 functionally associated with retrograde trafficking proteins in the trans-Golgi network (TGN), Arf-GAP with GTPase domain, ankyrin repeat, and pleckstrin homology domain-containing protein 2 (AGAP2), and ADP-ribosylation factor 1 (ARF1), together with HBV capsid, to open an alternative retrograde trafficking route for HBV from early endosomes (EEs) to the TGN and then to the endoplasmic reticulum (ER), thereby avoiding lysosomal degradation. Clinically, DOCK11 levels in liver biopsies from patients with chronic hepatitis B were significantly reduced by entecavir treatment, and this reduction correlated with HBV surface antigen levels.

          Conclusions

          HBV uses a retrograde trafficking route via EEs-TGN-ER for infection that is facilitated by DOCK11 and serves to maintain cccDNA. Therefore, DOCK11 is a potential therapeutic target to prevent persistent HBV infection.

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          Most cited references32

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          Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

          Huan Yan, Guocai Zhong, Guangwei Xu … (2012)
          Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157–165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV. DOI: http://dx.doi.org/10.7554/eLife.00049.001
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            ARF family G proteins and their regulators: roles in membrane transport, development and disease

            Julie Donaldson, Catherine Jackson (2011)
            Key Points The ADP-ribosylation factor (ARF) family of guanine-nucleotide-binding (G) proteins, including the ARF proteins, ARF-like (ARL) proteins and SAR1, regulates membrane traffic and organelle structure, and each family member is regulated through a cycle of GTP binding and GTP hydrolysis, which activate and inactivate, respectively, the G protein. Traditionally, ARFs have been characterized for their immediate effects in the recruitment of coat proteins to drive cargo sorting, the recruitment of enzymes that can alter membrane lipid composition and the regulation of cytoskeletal factors. Now, new roles for ARFs have been discovered at the Golgi complex, for example in driving lipid transport. ARL proteins are also being increasingly linked to coordination of trafficking with cytoskeletal processes, for example during ciliogenesis. There is particular interest in the mechanisms that control recruitment of the ARF guanine nucleotide exchange factors (GEFs) that mediate GTP binding to ARFs and, in the case of the cytohesin (also known as ARNO) GEF, membrane recruitment is coupled to relief of autoinhibition. GEFs such as cytohesin may also participate in a cascade of activation between particular pairs of ARFs. Traditionally, G protein signalling has been viewed as a linear pathway, with the GDP-bound form of an ARF protein being inactive; however, more recent studies have highlighted novel roles for these GDP-bound forms and have also shown that GEFs and GTPase-activating proteins (GAPs) themselves can engage in distinct signalling responses through scaffolding functions.
            Article 0 comments Cited 135 times – based on 0 reviews     Review now
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              Progress towards elimination goals for viral hepatitis

              Andrea Cox, Manal El-Sayed, Jia-Horng Kao … (2020)
              The global burden of viral hepatitis is substantial; in terms of mortality, hepatitis B virus and hepatitis C virus infections are on a par with HIV, malaria and tuberculosis, among the top four global infectious diseases. In 2016, the 194 Member States of the World Health Organization committed to eliminating viral hepatitis as a public health threat by 2030, with a particular focus on hepatitis B virus and hepatitis C virus infection. With only 10 years to go until the 2030 deadline is reached, and although much progress has been made towards elimination, there are still some important gaps in terms of policy and progress. In this Viewpoint, we asked a selection of scientists and clinicians working in the viral hepatitis field for their opinions on whether elimination of viral hepatitis by 2030 is feasible, what the key areas of progress are and what the focus for the next 10 years and beyond should be for viral hepatitis elimination.
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                Author and article information

                Contributors
                Masao Honda
                Journal
                Journal ID (nlm-ta): Cell Mol Gastroenterol Hepatol
                Journal ID (iso-abbrev): Cell Mol Gastroenterol Hepatol
                Title: Cellular and Molecular Gastroenterology and Hepatology
                Publisher: Elsevier
                ISSN (Electronic): 2352-345X
                Publication date Collection: 2023
                Publication date (Electronic): 19 October 2022
                Volume: 15
                Issue: 3
                Pages: 533-558
                Affiliations
                [1 ]Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
                [2 ]Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
                [3 ]Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan
                [4 ]Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
                [5 ]Purotech Bio Inc, Kanagawa, Japan
                [6 ]Department of Molecular Life Sciences, Doshisha University, Kyoto, Japan
                Author notes
                [∗ ] Correspondence Address correspondence to: Masao Honda, MD, PhD, Department of Clinical Laboratory Medicine, Graduate School of Medical Science, Kanazawa University, Kodatsuno 5-11-80, Kanazawa, 920-0942, Japan. mhonda@ 123456m-kanazawa.jp
                [∗]

                Authors share co-first authorship.

                Article
                Publisher Item ID: S2352-345X(22)00219-3
                DOI: 10.1016/j.jcmgh.2022.10.008
                PMC ID: 9868690
                PubMed ID: 36270602
                SO-VID: abe1cf1b-b12e-4fce-9f2b-e00c1f2a4f25
                Copyright © © 2022 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 24 December 2021
                Date accepted : 12 October 2022
                Categories
                Subject: Original Research

                Keywords: cccdna,dock11,retrograde trafficking,agap2,agap2, arf-gap with gtpase, ankyrin repeat, and pleckstrin homology domain-containing protein 2,arf1, adp ribosylation factor 1,bfa, brefeldin a,cccdna, covalently closed circular viral dna,cdc42, cell division cycle 42,chb, chronic hepatitis b,copi, coat protein i,dhr2, dock homology region 2,dock11, dedicator of cytokinesis 11,dox, doxycycline,ee, early endosome,er, endoplasmic reticulum,etv, entecavir,gef, guanine nucleotide exchange factor,geq, genome equivalents,gfp, green fluorescent protein,hbcag, hbv core antigen,hbcrag, hbv core-related antigen,hbsag, hbv surface antigen,hbv, hepatitis b virus,hcc, hepatocellular carcinoma,ig, immunoglobulin,le, late endosome,luc, luciferase,nl, nanoluc,ntcp, na/taurocholate cotransporting polypeptide,pbs, phosphate-buffered saline,pcr, polymerase chain reaction,pxb cells, primary human hepatocytes,pla, proximity ligation assay,rab7ko, rab7 knockout,rtd, real-time detection,shdock11, dock11 short hairpin rna,shrna, short hairpin rna,sirna, small interfering rna,stx, shiga toxin,tgn, trans-golgi network
                Data availability:
                Keywords: cccdna, dock11, retrograde trafficking, agap2, agap2, arf-gap with gtpase, ankyrin repeat, and pleckstrin homology domain-containing protein 2, arf1, adp ribosylation factor 1, bfa, brefeldin a, cccdna, covalently closed circular viral dna, cdc42, cell division cycle 42, chb, chronic hepatitis b, copi, coat protein i, dhr2, dock homology region 2, dock11, dedicator of cytokinesis 11, dox, doxycycline, ee, early endosome, er, endoplasmic reticulum, etv, entecavir, gef, guanine nucleotide exchange factor, geq, genome equivalents, gfp, green fluorescent protein, hbcag, hbv core antigen, hbcrag, hbv core-related antigen, hbsag, hbv surface antigen, hbv, hepatitis b virus, hcc, hepatocellular carcinoma, ig, immunoglobulin, le, late endosome, luc, luciferase, nl, nanoluc, ntcp, na/taurocholate cotransporting polypeptide, pbs, phosphate-buffered saline, pcr, polymerase chain reaction, pxb cells, primary human hepatocytes, pla, proximity ligation assay, rab7ko, rab7 knockout, rtd, real-time detection, shdock11, dock11 short hairpin rna, shrna, short hairpin rna, sirna, small interfering rna, stx, shiga toxin, tgn, trans-golgi network

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