Proteasome activator and antigen-processing aminopeptidases are regulated by virus-induced type I interferon in the hepatitis C virus-infected liver.
Many components of the class I antigen-processing pathway are thought to be regulated solely by interferon-gamma (IFN-gamma). Herein, we report type I IFN-mediated induction of proteasome activator (PA28) subunits alpha and beta, endoplasmic reticulum aminopeptidase 1 (ERAP1), ERAP2, and leucine aminopeptidase (LAP). This mechanism was initiated by either synthetic RNA (poly(I-C)) or by hepatitis C virus (HCV) RNA-mediated induction of type I IFN and abrogated by blocking of type I IFN. In serial liver biopsies of chimpanzees with acute HCV infection, increases in PA28 subunit and aminopeptidase mRNA levels correlated with intrahepatic type I IFN responses and preceded intrahepatic IFN-gamma responses by several weeks. Thus, viral RNA-induced type I IFN regulates the antigen-processing machinery early during viral infection and prior to IFN-gamma response. This mechanism may contribute to the high effectiveness of type I IFN-based therapies if administered early during acute HCV infection.
Shin
Eui-Cheol
EC
Immunology Section, Liver Diseases Branch, NIDDK, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
Seifert
Ulrike
U
Urban
Sabrina
S
Truong
Kim-Thuy
KT
Feinstone
Stephen M
SM
Rice
Charles M
CM
Kloetzel
Peter-M
PM
Rehermann
Barbara
B
D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017951:Antigen Presentation; D000998:Antiviral Agents / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000276:immunology / Q000378:metabolism; D006526:Hepatitis C / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D007931:Leucyl Aminopeptidase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D002679:Pan troglodytes; D011070:Poly I-C / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D000998:Antiviral Agents; D007370:Interferon Type I; D015778:Minor Histocompatibility Antigens; D009124:Muscle Proteins; C085047:PSME1 protein, human; D012333:RNA, Messenger; D007371:Interferon-gamma; D000626:Aminopeptidases; C464841:ERAP1 protein, human; C503944:ERAP2 protein, human; D007931:Leucyl Aminopeptidase; D046988:Proteasome Endopeptidase Complex; D011070:Poly I-C