Hepatitis B virus-induced calreticulin protein is involved in IFN resistance.
IFN-α is a widely used treatment for hepatitis B virus (HBV) infection, and IFN resistance caused by viral and/or host factors is currently a challenging clinical problem. A better understanding of the molecular mechanisms underlying IFN immunotherapy in the treatment of viral infection would be very beneficial clinically and is of immense clinical importance. Calreticulin (CRT) is an endoplasmic reticulum luminal calcium-binding chaperone that is involved in the regulation of calcium homoeostasis, the folding of newly synthesized proteins, and many other cellular functions. However, little is known about the role of CRT in HBV infection. In this study, we observed high levels of CRT expression in the sera and PBMCs of patients with HBV relative to those of healthy individuals. HBV upregulated the expression of CRT at the transcriptional level. Further investigation showed that HBV-induced CRT enhanced HBV replication by antagonizing the IFN pathway. CRT suppressed the production of endogenous IFN-α by reducing the nuclear translocation of IFN regulatory factor-7 but not IFN regulatory factor-3. Furthermore, CRT also suppressed the antiviral activity of IFN-α by inhibiting the phosphorylation of STAT1 and decreasing the expression of two IFN-α downstream effectors, protein kinase R and 2',5'-oligoadenylate synthetase. Our results offer new insights into the pathogenesis of HBV infection and may provide potential targets for anti-HBV therapy.
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
Xin
X
Yue
Hui
H
Wang
Fanpeng
F
Zhao
Shi
S
Liu
Jianguo
J
Wu
Wendan
W
Ren
Ying
Y
Zhu
D000328:Adult; D037282:Calreticulin / Q000502:physiology*; D060467:Disease Resistance / Q000276:immunology; D024882:Drug Resistance, Viral / Q000276:immunology*; D005260:Female; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007372:Interferons / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D014779:Virus Replication / Q000276:immunology; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D037282:Calreticulin; D016898:Interferon-alpha; D007372:Interferons; D019892:eIF-2 Kinase