Differential IFN-gamma stimulation of HLA-A gene expression through CRM-1-dependent nuclear RNA export.
IFNs regulate most MHC class I genes by stimulating transcription initiation. As shown previously, IFN-gamma controls HLA-A expression primarily at the posttranscriptional level. We have defined two 8-base sequences in a 39-nucleotide region in the 3'-transcribed region of the HLA-A gene that are required for the posttranscriptional response to IFN-gamma. Stimulation of HLA-A expression by IFN-gamma requires nuclear export of HLA-A mRNA by chromosome maintenance region 1 (CRM-1). Treatment of cells with leptomycin B, a specific inhibitor of CRM-1, completely inhibited IFN-gamma induction of HLA-A. Expression of a truncated, dominant-negative form of the nucleoporin NUP214/CAN, DeltaCAN, that specifically interacts with CRM-1, also prevented IFN-gamma stimulation of HLA-A, providing confirmation of the role of CRM-1. Increased expression of HLA-A induced by IFN-gamma also requires protein methylation, as shown by the fact that treatment of SK-N-MC cells or HeLa cells with the PRMT1 inhibitor 5'-methyl-5'-thioadenosine abolished the cellular response to IFN-gamma. In contrast with HLA-A, IFN-gamma-induced expression of the HLA class Ib gene, HLA-E, was not affected by either 5'-methyl-5'-thioadenosine or leptomycin B. These results provide proof of principle that it is possible to differentially modulate the IFN-gamma-induced expression of the HLA-E and HLA-A genes, whose products often mediate opposing effects on cellular immunity to tumor cells, pathogens, and autoantigens.
Browne
Sarah K
SK
Massey Cancer Center, Virginia Commonwealth University Medical Center, 401 College Street, Richmond, VA 23298, USA.
Roesser
James R
JR
Zhu
Sheng Zu
SZ
Ginder
Gordon D
GD
D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006680:HLA Antigens / Q000235:genetics; D015234:HLA-A Antigens / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D028884:Karyopherins / Q000502:physiology*; D008745:Methylation; D012313:RNA / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D000097606:Exportin 1 Protein; D000097625:HLA-E Antigens
D006680:HLA Antigens; D015234:HLA-A Antigens; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma; D028884:Karyopherins; D012313:RNA; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; D000097625:HLA-E Antigens