CD40 induces antigen transporter and immunoproteasome gene expression in carcinomas via the coordinated action of NF-kappaB and of NF-kappaB-mediated de novo synthesis of IRF-1.
Cancer cells may evade immune surveillance as a result of defective antigen processing and presentation. In this study, we demonstrate that CD40 ligation overcomes this defect through the coordinated action of the transcription factors NF-kappaB and interferon regulatory factor 1 (IRF-1). We show that unlike interferon signaling, which triggers the STAT1-mediated transcriptional activation of IRF-1, the ligation of CD40 in carcinomas induces the rapid upregulation of IRF-1 in a STAT1-independent but NF-kappaB-dependent manner. The transcriptional activation of IRF-1 is controlled largely by the recruitment of p65 (RelA) NF-kappaB to the IRF-1 promoter following the engagement of a TAK1/IkappaB kinase beta/IkappaBalpha signaling pathway downstream of CD40. NF-kappaB and de novo-synthesized IRF-1 converge to regulate the expression of genes involved in antigen processing and transport, as evident from the sequential recruitment of NF-kappaB and IRF-1 to the promoters of the genes encoding transporter for antigen processing 1 (TAP1), TAP2, tapasin, and low-molecular-mass polypeptides LMP2 and LMP10. Moreover, the RNA interference-mediated knockdown of IRF-1 reduced, whereas the inhibition of NF-kappaB abolished, the effects of CD40 on TAP1 and LMP2 upregulation in carcinoma cells. Collectively, these data reveal a novel "feed-forward" mechanism induced by NF-kappaB which ensures that acutely synthesized IRF-1 operates in concert with NF-kappaB to amplify the immunoproteasome and antigen-processing functions of CD40.
Moschonas
Aristides
A
Division of Basic Sciences, University of Crete Medical School, Heraklion, Crete, Greece.
Kouraki
Maria
M
Knox
Pauline G
PG
Thymiakou
Efstathia
E
Kardassis
Dimitris
D
Eliopoulos
Aristides G
AG
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D017951:Antigen Presentation / Q000235:genetics; D019013:CD40 Antigens / Q000276:immunology*; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis* / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology*; D014176:Protein Biosynthesis; D021381:Protein Transport; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D015854:Up-Regulation
D018528:ATP-Binding Cassette Transporters; D019013:CD40 Antigens; D050856:Interferon Regulatory Factor-1; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D051996:Transcription Factor RelA; C477327:transporter associated with antigen processing (TAP); C071313:LMP-2 protein; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex