DC-STAMP: :Localization and Function in Dendritic Cells
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S.l. : s.n.
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RU Radboud Universiteit Nijmegen, 11 november 2009
Promotor : Adema, G.J.
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SubjectONCOL 3: Translational research NCMLS 2: Immune Regulation
Many studies have been performed to elucidate the functional role of the DCs in orchestrating immune responses. The main goal of this thesis is to increase our understanding of DC immunobiology at the molecular level. A molecular approach was followed to unravel the role of two novel molecules in DC function. We report characterization of DC-SCRIPT as a putative transcriptional regulator having Zinc fingers mediating DNA binding flanked by a prolin-rich region and an acidic region playing possible roles in the regulation of transcription. Furthermore, the thesis focuses on the previously characterized DC-specific gene DC-STAMP. Our data show that DC-STAMP, both mouse and human homologue, localizes to the Endoplasmic Reticulum (ER). The myeloid precursor cell differentiates into two lineages. DC-STAMP is expressed in cells of the lineage generating macrophages, DCs, and osteoclasts but not the granulocyte lineage. Our data show that DC-STAMP selectively suppresses granulocyte development suggesting that its involvement in myeloid development. To gain molecular insight into DC-STAMP function, two DC-STAMP interacting proteins were identified. The amplified in osteosarcoma 9 (OS9) is reported to interact with DC-STAMP, and both proteins co-localize in the ER. The data indicate that OS9 is critically involved in the modulation of ER-to-Golgi transport of DC-STAMP in response to TLR triggering. Furthermore, Luman was characterized as a second interacting partner of DC-STAMP. Luman is an ER-resident transcription factor, which undergoes Regulated Intramembrane Proteolysis. During this process Luman translocates from ER to the Golgi apparatus, where it is cleaved followed by translocation of the liberated active part of Luman to the nucleus. This study unravels a role for DC-STAMP in Luman activation and suggests that this pathway is activated in DCs in response to DC maturation stimuli. Taken together, the implications of the results described in the thesis towards a better understanding of the DC immunobiology are discussed.
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