Cellular Membrane Trafficking Machineries Used by the Hepatitis Viruses

Inoue, Jun; Ninomiya, Masashi; Shimosegawa, Tooru; McNiven, Mark A.

doi:10.1002/hep.29785

Cited by 22 publications

(24 citation statements)

References 47 publications

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“…HBV encodes three envelope glycoproteins, small (S), middle (M) and large(L) 8 . The preS1 domain of the L protein binds heparan sulfate proteoglycan (HSPG) 9–11 that precedes high-affinity virus interaction with NTCP. Synthetic peptides mimicking the preS1 binding site for NTCP, such as Myrcludex-B (MyrB) inhibit HBV infection 12,13 and a recent phase II clinical trial efficacy in HBV patients co-infected with hepatitis delta virus 14 .…”

Section: Introductionmentioning

confidence: 99%

Synchronized infection identifies early rate-limiting steps in the hepatitis B virus life cycle

Chakraborty

Henning

et al. 2020

Preprint

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24Hepatitis B virus (HBV) is an enveloped DNA virus that contains a partially double-stranded relaxed circular (rc) 25 DNA. Upon infection, rcDNA is delivered to the nucleus where it is repaired to covalently closed circular (ccc) DNA 26 that serves as the transcription template for all viral RNAs. Our understanding of HBV particle entry dynamics and 27 host pathways regulating intracellular virus trafficking and cccDNA formation is limited. The discovery of sodium 28 taurocholate co-transporting peptide (NTCP) as the primary receptor allows studies on these early steps in viral 29 life cycle. We employed a synchronized infection protocol to quantify HBV entry kinetics. HBV attachment to cells 30 at 4°C is independent of NTCP, however, subsequent particle uptake is NTCP-dependent and reaches saturation 31 at 12h post-infection. HBV uptake is clathrin-and dynamin dependent with actin and tubulin playing a role in the 32 first 6h of infection. Cellular fractionation studies demonstrate HBV DNA in the nucleus within 6h of infection and 33 cccDNA was first detected at 24h post-infection. Our studies show the majority (83%) of cell bound particles enter 34 HepG2-NTCP cells, however, only a minority (<1%) of intracellular rcDNA was converted to cccDNA, highlighting 35 this as a rate-limiting in establishing infection in vitro. This knowledge highlights the deficiencies in our in vitro cell 36 culture systems and will inform the design and evaluation of physiologically relevant models that support efficient 37 HBV replication. 39Hepatitis B Virus (HBV) infects 257 million individuals worldwide and is a major driver of end-stage liver disease, 41 cirrhosis, and hepatocellular carcinoma (HCC). HBV is an enveloped DNA and prototypic member of the 42 hepadnaviridae that establishes its genome as an episomal, covalently closed circular DNA (cccDNA) in the nucleus 43 of infected hepatocytes. Current treatments suppress viral replication but are not curative, largely due to the 44 persistence of the cccDNA transcriptional template and failure to mount an effective anti-viral immune response 1 . 45In most cases, treatment is life-long and patients may still develop HCC 2 , highlighting a clinical need for new 46 curative therapies 3 . Despite its central role in the HBV life cycle our understanding of the host factors regulating 47 cccDNA genesis and half-life is limited 4 . 49Viral entry into a host cell represents the first step in the infectious life cycle and is mediated via specific 50 interactions between virus encoded proteins and cellular receptors that define internalization pathways 5 . The 51 discovery that sodium taurocholate co-transporting polypeptide (NTCP) acts as a receptor for HBV 6,7 enabled the 52 development of in vitro culture systems that support the complete HBV replication cycle. HBV encodes three 53 envelope glycoproteins, small (S), middle (M) and large(L) 8 . The preS1 domain of the L protein binds heparan 54 sulfate proteoglycan (HSPG) 9-11 that precedes high-affinity virus interaction with NTCP....

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Section: Introductionmentioning

confidence: 99%

Synchronized infection identifies early rate-limiting steps in the hepatitis B virus life cycle

Chakraborty

Henning

et al. 2020

Preprint

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“…Estimates from the 2017 Global Hepatitis Report (World Health Organization, 2017) suggest that 257 million (3.5% of the global population) or 71 million (1% of the global population) individuals are chronically infected with HBV or HCV, respectively. These staggering statistics underlie an urgent need for understanding the cell biology and hepatocellular life cycles of these and other hepatotropic viruses (Inoue et al, 2018).…”

Section: The Hepatocyte As a Viral Incubatormentioning

confidence: 99%

The cell biology of the hepatocyte: A membrane trafficking machine

Schulze

Schott

Casey

et al. 2019

Journal of Cell Biology

Self Cite

149

102

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The liver performs numerous vital functions, including the detoxification of blood before access to the brain while simultaneously secreting and internalizing scores of proteins and lipids to maintain appropriate blood chemistry. Furthermore, the liver also synthesizes and secretes bile to enable the digestion of food. These diverse attributes are all performed by hepatocytes, the parenchymal cells of the liver. As predicted, these cells possess a remarkably well-developed and complex membrane trafficking machinery that is dedicated to moving specific cargos to their correct cellular locations. Importantly, while most epithelial cells secrete nascent proteins directionally toward a single lumen, the hepatocyte secretes both proteins and bile concomitantly at its basolateral and apical domains, respectively. In this Beyond the Cell review, we will detail these central features of the hepatocyte and highlight how membrane transport processes play a key role in healthy liver function and how they are affected by disease.

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“…Direct evidences suggesting chronic inflammation, especially hepatitis B and hepatitis C, are the risk factor for HCC. Patients who have those diseases will get more risk to Inflammation cytokines and chemokines: TNF-a, IL-6, IL-1b, IL-10, COX-2, VEGF, HIF-1a, MMPS, Erk, Akt, TGF-a/b1, JNK, ERK, P38, ELK-1, AP-1, TCF, CD95, IL-1b Liver cancer develop HCC [11] . The development of HCC is a multistep process.…”

Section: Inflammation and Liver Cancermentioning

confidence: 99%

Understanding the inflammation-cancer transformation in the development of primary liver cancer

Chen¹,

Hu²,

Xu³

et al. 2018

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Primary liver cancer is one of the leading causes of cancer-related deaths worldwide. China has more than 55% liver cancer cases globally. The development of hepatocellular carcinoma (HCC) was caused by a variety of risks factors, including chronic inflammation by virus, alcohol consumption and non-alcoholic steatohepatitis. Emerging evidence has notarized inflammation as a critical component of HCC progression. The development of HCC is a multistep process which may originate from liver chronic injury and inflammation to subsequent fibrosis and/or cirrhosis and finally HCC. A large number of studies indicate that chemokines and cytokines are candidates linking molecules between inflammation and liver cancer. Here, we will describe a few of the key cytokines and chemokines and signal pathways which are involved in the inflammation of HCC. Inhibitors of inflammation for the prevention and overcoming antitumor immunity for treatment of liver cancer are promising candidates for the future management of patients with HCC.

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Cellular Membrane Trafficking Machineries Used by the Hepatitis Viruses

Cited by 22 publications

References 47 publications

Synchronized infection identifies early rate-limiting steps in the hepatitis B virus life cycle

Synchronized infection identifies early rate-limiting steps in the hepatitis B virus life cycle

The cell biology of the hepatocyte: A membrane trafficking machine

Understanding the inflammation-cancer transformation in the development of primary liver cancer

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