Cutting edge: induction of the antigen-processing enzyme IFN-gamma-inducible lysosomal thiol reductase in melanoma cells Is STAT1-dependent but CIITA-independent.
Presentation and CD4(+) T cell responses to Ag in the context of MHC class II molecules require processing of native proteins into short peptide fragments. Within this pathway, IFN-gamma-inducible lysosomal thiol reductase (GILT) functions to catalyze thiol bond reduction, thus unfolding native protein Ag and facilitating further processing via cellular proteases. In contrast with professional APCs such as B cells, class II-positive human melanomas expressed relatively little to no GILT protein or mRNA. Tumor cell GILT expression was partially restored with IFN-gamma treatment but unlike other genes required for class II Ag presentation, GILT was not regulated by CIITA. Rather, studies revealed STAT1 plays a direct role in IFN-gamma-inducible GILT expression. These results define a molecular mechanism for the uncoupled regulation of MHC class II genes and the processing enzyme GILT in human melanomas.
O'Donnell
Patrick W
PW
Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Haque
Azizul
A
Klemsz
Michael J
MJ
Kaplan
Mark H
MH
Blum
Janice S
JS
D017951:Antigen Presentation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005802:Genes, MHC Class II; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D010088:Oxidoreductases; C056859:IFI30 protein, human; D050862:Oxidoreductases Acting on Sulfur Group Donors