The chaperone dynein LL1 mediates cytoplasmic transport of empty and mature hepatitis B virus capsidsAuthor links open overlay panelQuentinOsseman12†LaraGallucci12ShellyAu3‡ChristianCazenave12ElodieBerdance12Marie-LiseBlondot12AuréliaCassany12DominiqueBégu12JessicaRagues12CindyAknin12IrinaSominskaya4AndrisDishlers4BirgitRabe5§FenjaAnderson56NellyPanté3MichaelKann1257
https://doi.org/10.1016/j.jhep.2017.10.032Get rights and content
Highlights•Identification of the binding partner mediating cytoplasmic transport of HBV capsids. •Transport was restricted to mature and empty capsids. •The domains on capsid and dynein LL1 were identified. •Transport inhibition may block infection and increase elimination of infected hepatocytes.
Background & AimsHepatitis B virus (HBV) has a DNA genome but replicates within the nucleus by reverse transcription of an RNA pregenome, which is converted to DNA in cytoplasmic capsids. Capsids in this compartment are correlated with inflammation and epitopes of the capsid protein core (Cp) are a major target for T cell-mediated immune responses. We investigated the mechanism of cytoplasmic capsid transport, which is important for infection but also for cytosolic capsid removal.
MethodsWe used virion-derived capsids containing mature rcDNA (matC) and empty capsids (empC). RNA-containing capsids (rnaC) were used as a control. The investigations comprised pull-down assays for identification of cellular interaction partners, immune fluorescence microscopy for their colocalization and electron microscopy after microinjection to determine their biological significance.
ResultsmatC and empC underwent active transport through the cytoplasm towards the nucleus, while rnaC was poorly transported. We identified the dynein light chain LL1 as a functional interaction partner linking capsids to the dynein motor complex and showed that there is no compensatory transport pathway. Using capsid and dynein LL1 mutants we characterized the required domains on the capsid and LL1.
ConclusionsThis is the first investigation on the detailed molecular mechanism of how matC pass the cytoplasm upon infection and how empC can be actively removed from the cytoplasm into the nucleus. Considering that hepatocytes with cytoplasmic capsids are better recognized by the T cells, we hypothesize that targeting capsid DynLL1-interaction will not only block HBV infection but also stimulate elimination of infected cells.
Lay summaryIn this study, we identified the molecular details of HBV translocation through the cytoplasm. Our evidence offers a new drug target which could not only inhibit infection but also stimulate immune clearance of HBV infected cells.
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发表于 2018-2-17 10:59