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Differential Expression Regulation of the and Subunits of the PA28 Proteasome Activator in Mature Dendritic Cells¹

Ferry Ossendorp^2,3,*, Nathalie Fu^2,*, Marcel Camps^*, Francesca Granucci^||, Sam J. P. Gobin^*, Peter J. van den Elsen^*, Danita Schuurhuis^*, Gosse J. Adema, Grayson B. Lipford, Tomoki Chiba, Alice Sijts^¶, Peter-M. Kloetzel^¶, Paola Ricciardi-Castagnoli^|| and Cornelis J. M. Melief^*

Departments of^* Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands; Department of Tumor Immunology, Nij-megen Centre for Molecular Life Sciences, University Medical Center, Nijmegen, The Netherlands; Institute for Medical Microbiology and Immunology, Technical University of Munich, Munich, Germany; Department of Molecular Oncology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; ^¶ Institute of Biochemistry, Charité, Humboldt University Berlin, Berlin, Germany; and ^|| Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy

Activation of dendritic cells (DC) by Th-dependent (CD40) or -independent (LPS, CpG, or immune complexes) agonistic stimuli strongly enhances the expression of the proteasome activator PA28 complex. Upon activation of DC, increased MHC class I presentation occurred of the melanocyte-associated epitope tyrosinase-related protein 2_180-188 in a PA28-dependent manner. In contrast to other cell types, regulation of PA28 expression in DC after maturation was found to be IFN- independent. In the present study, we show that expression of PA28 and subunits was differentially regulated. Firstly, PA28 expression is high in both immature and mature DC. In contrast, PA28 expression is low in immature DC and strongly increased in mature DC. Secondly, we show the presence of a functional NF-B site in the PA28 promoter, which is absent in the PA28 promoter, indicating regulation of PA28 expression by transcription factors of the NF-B family. In addition, glycerol gradient analysis of DC lysates revealed elevated PA28 complex formation upon maturation. Thus, induction of PA28 expression allows proper PA28 complex formation, thereby enhancing proteasome activity in activated DC. Therefore, maturation of DC not only improves costimulation but also MHC class I processing. This mechanism enhances the CD8⁺ CTL (cross)-priming capacity of mature DC.

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