title: PRAME is a golgi-targeted protein that associates with the Elongin BC complex and is upregulated by interferon-gamma and bacterial PAMPs.
abstract: Preferentially expressed antigen in melanoma (PRAME) has been described as a cancer-testis antigen and is associated with leukaemias and solid tumours. Here we show that PRAME gene transcription in leukaemic cell lines is rapidly induced by exposure of cells to bacterial PAMPs (pathogen associated molecular patterns) in combination with type 2 interferon (IFNγ). Treatment of HL60 cells with lipopolysaccharide or peptidoglycan in combination with IFNγ resulted in a rapid and transient induction of PRAME transcription, and increased association of PRAME transcripts with polysomes. Moreover, treatment with PAMPs/IFNγ also modulated the subcellular localisation of PRAME proteins in HL60 and U937 cells, resulting in targeting of cytoplasmic PRAME to the Golgi. Affinity purification studies revealed that PRAME associates with Elongin B and Elongin C, components of Cullin E3 ubiquitin ligase complexes. This occurs via direct interaction of PRAME with Elongin C, and PRAME colocalises with Elongins in the Golgi after PAMP/IFNγ treatment. PRAME was also found to co-immunoprecipitate core histones, consistent with its partial localisation to the nucleus, and was found to bind directly to histone H3 in vitro. Thus, PRAME is upregulated by signalling pathways that are activated in response to infection/inflammation, and its product may have dual functions as a histone-binding protein, and in directing ubiquitylation of target proteins for processing in the Golgi.
authors: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, United Kingdom.
authors: Frances R
authors: FR
authors: Wadelin
authors: Joel
authors: J
authors: Fulton
authors: Hilary M
authors: HM
authors: Collins
authors: Nikolaos
authors: N
authors: Tertipis
authors: Andrew
authors: A
authors: Bottley
authors: Keith A
authors: KA
authors: Spriggs
authors: Franco H
authors: FH
authors: Falcone
authors: David M
authors: DM
authors: Heery
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D001419:Bacteria / Q000378:metabolism*; D002460:Cell Line; D000075065:Elongin; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D013058:Mass Spectrometry; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051192:Receptors, Pattern Recognition / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000951:Antigens, Neoplasm; C000616396:ELOB protein, human; C000616395:ELOC protein, human; D000075065:Elongin; D006657:Histones; D008070:Lipopolysaccharides; D046912:Multiprotein Complexes; C404944:PRAME protein, human; D051192:Receptors, Pattern Recognition; D014157:Transcription Factors; D007371:Interferon-gamma