Nuclear localisation of CIITA is controlled by a carboxy terminal leucine-rich repeat region.
Regulation of both IFN-gamma inducible and constitutive MHC class II gene transcription is under the control of CIITA. This master regulator is synthesised in the cytosol and must translocate to the nucleus in order to activate class II gene transcription. Here, we demonstrate that, in a patient deficient in MHC class II gene expression, a single missense mutation results in sequestration of CIITA within the cytosol. The mutation is situated in a region that bears homology to the beta strand domain of ribonuclease inhibitor-like leucine-rich repeat (LRR) motifs. Deletion and mutagenesis analysis suggest that structural integrity of this region is required for efficient nuclear localisation. Importantly, we show that in the absence of amino terminal domains, the carboxy terminal LRR region is sufficient to efficiently target GFP chimeric proteins to the nucleus. CIITA therefore encodes multiple domains that can, in isolation, efficiently target to the nuclear compartment.
Towey
Michael
M
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
Kelly
Adrian P
AP
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002467:Cell Nucleus / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004058:Diffusion; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D007930:Leucine / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010649:Phenylalanine / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D012694:Serine / Q000235:genetics / Q000502:physiology; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D008164:Luminescent Proteins; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D049452:Green Fluorescent Proteins; D012694:Serine; D010649:Phenylalanine; D007930:Leucine