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N-terminal destruction signals lead to rapid degradation of the major histocompatibility complex class II transactivator CIITA

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Schnappauf,  Felix
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Hake,  Sandra B.
Spemann Laboratory, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Camacho Carvajal,  Margarita M.
Max Planck Society;

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Steimle,  Viktor
Spemann Laboratory, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Schnappauf, F., Hake, S. B., Camacho Carvajal, M. M., Bontron, S., Lisowska-Grospierre, B., & Steimle, V. (2003). N-terminal destruction signals lead to rapid degradation of the major histocompatibility complex class II transactivator CIITA. European Journal of Immunology, 33(8), 2337-2347.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-9510-6
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.