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HBV secretion is regulated through the activation of endocytic and autophagic compartments mediated by Rab7 stimulation.

ABSTRACT: The cellular mechanisms by which hepatitis B virus (HBV) is assembled and exported are largely undefined. Recently, it has been suggested that these steps require the multivesicular body (MVB) and the autophagic machinery. However, the mechanisms by which HBV might regulate these compartments are unclear. In this study, we have found that by activating Rab7a, HBV alters its own secretion by inducing dramatic changes in the morphology of MVB and autophagic compartments. These changes are characterized by the formation of numerous tubules that are dependent upon the increase in Rab7 activity observed in the HBV-expressing HepG2.2.15 cells compared to HepG2 cells. Interestingly, transfection-based expression of the five individual viral proteins indicated that the precore protein, which is a precursor of HBeAg, was largely responsible for the increased Rab7 activity. Finally, small interfering RNA (siRNA)-mediated depletion of Rab7 significantly increased the secretion of virions, suggesting that reduced delivery of the virus to the lysosome facilitates viral secretion. These findings provide novel evidence indicating that HBV can regulate its own secretion through an activation of the endo-lysosomal and autophagic pathway mediated by Rab7 activation.

SUBMITTER: Inoue J

PROVIDER: S-EPMC4446738 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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HBV secretion is regulated through the activation of endocytic and autophagic compartments mediated by Rab7 stimulation.

Inoue Jun J Krueger Eugene W EW Chen Jing J Cao Hong H Ninomiya Masashi M McNiven Mark A MA

Journal of cell science 20150313 9

The cellular mechanisms by which hepatitis B virus (HBV) is assembled and exported are largely undefined. Recently, it has been suggested that these steps require the multivesicular body (MVB) and the autophagic machinery. However, the mechanisms by which HBV might regulate these compartments are unclear. In this study, we have found that by activating Rab7a, HBV alters its own secretion by inducing dramatic changes in the morphology of MVB and autophagic compartments. These changes are characte ...[more]

PMID: 25770103

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Project description:Hepatitis B virus (HBV) particles are thought to be secreted from hepatocytes through multivesicular bodies (MVBs); however, the cellular trafficking mechanisms prior to this process remain elusive. It has been reported that CCDC88A/GIV expression, which is involved in multiple aspects of vesicular trafficking, changes dynamically at different phases of chronic HBV infection. In this study, we focused on the role of CCDC88A/GIV in HBV replication. In the liver tissues of chronically HBV-infected patients, HBV infection significantly enhanced CCDC88A/GIV expression, and increased endoplasmic reticulum (ER) stress and autophagosome formation without changing endosome formation. Additionally, colocalization of SHBsAg with early endosomes (~30.2%) far exceeded that with autophagosomes (~3.2%). In hepatoma cells, CCDC88A/GIV and its downstream proteins, DNM2 (dynamin 2; a CCDC88A/GIV effector), CLTC and RAB5A significantly enhanced HBV replication and endosome formation but inhibited autophagosome formation. Blocking endocytosis disrupted HBsAg trafficking to endosomes and caused its accumulation in the ER lumen, which triggered ER stress to initiate the unfolded protein response (UPR). Therefore, HBsAg trafficking into autophagosomes was increased, and the lysosomal activity and maturation, which was inhibited by HBV infection, were restored. Meanwhile, core particles were prevented from entering MVBs. CCDC88A/GIV and its other effector, GNAI3, decreased autophagic flux by enhancing the insulin-induced AKT-MTOR pathway, thereby inhibiting HBV antigens autophagic degradation. In conclusion, CCDC88A/GIV enhanced HBV replication by increasing endosomal trafficking and reducing autophagic degradation of HBV antigens, suggesting that CCDC88A/GIV-mediated endosomal trafficking plays an important role in HBV replication and progeny secretion.Abbreviations: ACTB: actin beta; AO: acridine orange; ATF6: activating transcription factor 6; CCDC88A/GIV: coiled-coil domain containing 88A; CLTC: clathrin heavy chain; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DNM2: dynamin 2; ER: endoplasmic reticulum; ERN1: endoplasmic reticulum to nucleus signaling 1; EIF2A: eukaryotic translation initiation factor 2A; FBS: fetal bovine serum; GNAI3: G protein subunit alpha i3; HBV: hepatitis B virus; HBV RIs: HBV replication intermediates; HBcAg: HBV core protein; HBsAg: HBV surface antigen; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MVBs: multivesicular bodies; MTOR: mechanistic target of rapamycin kinase; PDI: protein disulfide isomerase; PHH: primary human hepatocyte; pSM2: a HBV replication-competent plasmid; HSPA5/BIP: heat shock protein family A (Hsp70) member 5; SQSTM1/p62: sequestosome 1; siRNA: small interfering RNA; SEM: standard error of the mean; UPR: unfolded protein response.

Dataset Information

HBV secretion is regulated through the activation of endocytic and autophagic compartments mediated by Rab7 stimulation.

Publications

HBV secretion is regulated through the activation of endocytic and autophagic compartments mediated by Rab7 stimulation.

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