MITA/STING and Its Alternative Splicing Isoform MRP Restrict Hepatitis B Virus Replication

PLoS One. 2017 Jan 5;12(1):e0169701. doi: 10.1371/journal.pone.0169701. eCollection 2017.

Abstract

An efficient clearance of hepatitis B virus (HBV) requires the coordinated work of both the innate and adaptive immune responses. MITA/STING, an adapter protein of the innate immune signaling pathways, plays a key role in regulating innate and adaptive immune responses to DNA virus infection. Previously, we identified an alternatively spliced isoform of MITA/STING, called MITA-related protein (MRP), and found that MRP could specifically block MITA-mediated interferon (IFN) induction while retaining the ability to activate NF-κB. Here, we asked whether MITA/STING and MRP were able to control the HBV replication. Both MITA/STING and MRP significantly inhibited HBV replication in vitro. MITA overexpression stimulated IRF3-IFN pathway; while MRP overexpression activated NF-κB pathway, suggesting these two isoforms may inhibit HBV replication through different ways. Using a hydrodynamic injection (HI) mouse model, we found that HBV replication was reduced following MITA/STING and MRP expression vectors in mice and was enhanced by the knockout of MITA/STING (MITA/STING-/-). The HBV specific humoral and CD8+ T cell responses were impaired in MITA/STING deficient mice, suggesting the participation of MITA/STING in the initiation of host adaptive immune responses. In summary, our data suggest that MITA/STING and MRP contribute to HBV control via modulation of the innate and adaptive responses.

MeSH terms

  • Alternative Splicing / genetics
  • Alternative Splicing / physiology*
  • Animals
  • Blotting, Northern
  • Blotting, Western
  • Enzyme-Linked Immunosorbent Assay
  • Hepatitis B virus / genetics
  • Hepatitis B virus / physiology*
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Liver / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism*
  • RNA Interference
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Virus Replication / genetics
  • Virus Replication / physiology

Substances

  • Membrane Proteins
  • Protein Isoforms
  • STING1 protein, human

Grants and funding

This work was supported by grants from the National Nature Science Foundation of China (31621061, 81461130019) and the National Basic Research Priorities Program of China (2013CB911100, 2012CB519001). Rongjuna Pei is supported by the National Nature Science Foundation of China (81672021).