title: N-terminal destruction signals lead to rapid degradation of the major histocompatibility complex class II transactivator CIITA.
abstract: Major histocompatibility complex (MHC) class II molecules play an essential role for the cellular immune response by presenting peptide antigens to CD4(+) T cells. MHC class II molecules and genes show a highly complex expression pattern, which is orchestrated through a master regulatory factor, called CIITA (class II transactivator). CIITA controls MHC class II expression not only qualitatively, but also quantitatively, and has therefore a direct influence on the CD4 T cell-dependent immune response. CIITA is itself tightly regulated not only on the transcriptional level, but as we show here also on the protein level. CIITA is subjected to a very rapid protein turnover and shows a half-life of about 30 min. Inhibition of degradation by proteasome inhibitors and the identification of ubiquitylated CIITA intermediates indicate that the degradation of CIITA is mediated by the ubiquitin-proteasome system. We identified two regions mediating degradation within the N-terminal domain of CIITA. N-terminal fusions or deletions stabilized CIITA, indicating that the N termini contribute to degradation. Several non-functional CIITA mutants are partially stabilized, but we provide evidence that transcriptional activity of CIITA is not directly linked to degradation.
authors.affiliation: Hans-Spemann-Laboratories, Max-Planck-Institut für Immunbiologie, Freiburg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Schnappauf
authors.forename: Sandra B
authors.initials: SB
authors.lastname: Hake
authors.forename: Margarita M
authors.initials: MM
authors.lastname: Camacho Carvajal
authors.forename: Séverine
authors.initials: S
authors.lastname: Bontron
authors.forename: Barbara
authors.initials: B
authors.lastname: Lisowska-Grospierre
authors.forename: Viktor
authors.initials: V
authors.lastname: Steimle
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004355:Drug Stability; D005802:Genes, MHC Class II; D006207:Half-Life; D006801:Humans; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D021382:Protein Sorting Signals / Q000235:genetics; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D015534:Trans-Activators / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C083728:MHC class II transactivator protein; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D021382:Protein Sorting Signals; D015534:Trans-Activators; D025801:Ubiquitin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex