Nuclear export of human hepatitis B virus core protein and pregenomic RNA depends on the cellular NXF1-p15 machinery

PLoS One. 2014 Oct 31;9(10):e106683. doi: 10.1371/journal.pone.0106683. eCollection 2014.


Hepatitis B virus (HBV) core protein (HBc) can shuttle between nucleus and cytoplasm. Cytoplasm-predominant HBc is clinically associated with severe liver inflammation. Previously, we found that HBc arginine-rich domain (ARD) can associate with a host factor NXF1 (TAP) by coimmunoprecipitation. It is well known that NXF1-p15 heterodimer can serve as a major export receptor of nuclear mRNA as a ribonucleoprotein complex (RNP). In the NXF1-p15 pathway, TREX (transcription/export) complex plays an important role in coupling nuclear pre-mRNA processing with mRNA export in mammalian cells. Here, we tested the hypothesis whether HBc and HBV specific RNA can be exported via the TREX and NXF1-p15 mediated pathway. We demonstrated here that HBc can physically and specifically associate with TREX components, and the NXF1-p15 export receptor by coimmunoprecipitation. Accumulation of HBc protein in the nucleus can be induced by the interference with TREX and NXF1-p15 mediated RNA export machinery. HBV transcripts encodes a non-spliced 3.5 kb pregenomic RNA (pgRNA) which can serve as a template for reverse transcription. Cytoplasmic HBV pgRNA appeared to be reduced by siRNA treatment specific for the NXF1-p15 complex by quantitative RT-qPCR and Northern blot analyses. This result suggests that the pgRNA was also exported via the NXF1-p15 machinery. We entertain the hypothesis that HBc protein can be exported as an RNP cargo via the mRNA export pathway by hijacking the TREX and NXF1-p15 complex. In our current and previous studies, HBc is not required for pgRNA accumulation in the cytoplasm. Furthermore, HBc ARD can mediate nuclear export of a chimeric protein containing HBc ARD in a pgRNA-independent manner. Taken together, it suggests that while both pgRNA and HBc protein exports are dependent on NXF1-p15, they are using the same export machinery in a manner independent of each other.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Cell Line
  • Cell Nucleus
  • Cytoplasm / genetics
  • DNA Replication
  • Hepatitis B virus / genetics
  • Hepatitis B virus / metabolism*
  • Host-Pathogen Interactions
  • Humans
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Nuclear Export Signals
  • Nucleocytoplasmic Transport Proteins / genetics
  • Nucleocytoplasmic Transport Proteins / metabolism*
  • Protein Structure, Tertiary
  • RNA
  • RNA Transport* / genetics
  • RNA, Messenger / genetics
  • RNA, Small Interfering
  • RNA, Viral / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Viral Core Proteins / genetics
  • Viral Core Proteins / metabolism*


  • Multiprotein Complexes
  • NXF1 protein, human
  • Nuclear Export Signals
  • Nucleocytoplasmic Transport Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA, Viral
  • RNA-Binding Proteins
  • Viral Core Proteins
  • RNA

Grant support

Funding sources include a grant to CS from Academia Sinica, Taiwan (; National Health Research Institute (NHRI Taiwan) Grant Number: NHRI-EX102-10203BI to CS (; and Ministry of Science and Technology (MOST Taiwan) grant to CS. ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.