Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection
Eui-Cheol Shin, Ulrike Seifert, Takanobu Kato, Charles M. Rice, Stephen M. Feinstone, Peter-M. Kloetzel, Barbara Rehermann
Eui-Cheol Shin, Ulrike Seifert, Takanobu Kato, Charles M. Rice, Stephen M. Feinstone, Peter-M. Kloetzel, Barbara Rehermann
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Research Article Immunology

Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection

Abstract

IFN-γ is known as the initial and primary inducer of immunoproteasomes during viral infections. We now report that type I IFN induced the transcription and translation of immunoproteasome subunits, their incorporation into the proteasome complex, and the generation of an immunoproteasome-dependent CD8 T cell epitope in vitro and provide in vivo evidence that this mechanism occurs prior to IFN-γ responses at the site of viral infection. Type I IFN–mediated generation of immunoproteasomes was initiated by either poly(I:C) or HCV RNA in human hepatoma cells and was inhibited by neutralization of type I IFN. In serial liver biopsies of chimpanzees with acute HCV infection, increases in immunoproteasome subunit mRNA preceded intrahepatic IFN-γ responses by several weeks, instead coinciding with intrahepatic type I IFN responses. Thus, viral RNA–induced innate immune responses regulate the antigen-processing machinery, which occurs prior to the detection of IFN-γ at the site of infection. This mechanism may contribute to the high effectiveness (95%) of type I IFN–based therapies if administered early during HCV infection.

Authors

Eui-Cheol Shin, Ulrike Seifert, Takanobu Kato, Charles M. Rice, Stephen M. Feinstone, Peter-M. Kloetzel, Barbara Rehermann

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Figure 1

Type I IFN induces the expression of immunoproteasome subunits in vitro.

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Type I IFN induces the expression of immunoproteasome subunits in vitro....
(A) Huh-7 cells were treated with 3 ng/ml IFN-α–con1 (squares) or 10 ng/ml (200 U/ml) IFN-γ (triangles) for the indicated time periods, after which the mRNA levels of immunoproteasome subunits were quantified by real-time PCR. mRNA levels were normalized to endogenous references (GAPDH and β-actin) and expressed as fold increase over pretreatment levels. The β7 subunit was measured as a control. (B) Huh-7 cells were treated with the indicated doses of IFN-α–con1 or IFN-γ for 48 hours, and Western blot analysis was performed to detect immunoproteasome subunits. The α4 subunit was analyzed as a control. (C) Primary human hepatocytes were treated with 3 ng/ml IFN-α–con1 or 10 ng/ml IFN-γ for the indicated time periods prior to Western blot analysis. (D) Huh-7 cells were treated with 1.8 ng/ml (500 U/ml) IFN-α2a, 3 ng/ml IFN-α–con1, 3 ng/ml IFN-β, or 10 ng/ml IFN-γ for the indicated time periods, and Western blot analysis was performed to detect immunoproteasome subunits. The density of the Western blot bands was quantified and expressed as percent of the density of the α4 control band.