Regulation of human β2-microglobulin transactivation in hematopoietic cells

Abstract

␤ 2 -Microglobulin (␤ 2 m) is a chaperone of major histocompatibility complex (MHC) class I (-like) molecules that play a central role in antigen presentation, immunoglobulin transport, and iron metabolism. It is therefore of importance that ␤ 2 m is adequately expressed in cells that perform these functions, such as hematopoietic cells. In this study, we investigated the transcriptional regulation of ␤ 2 m in lymphoid and myeloid cell lines through a promoter containing a putative E box, Ets/interferon-stimulated response element (ISRE), and B site. Here we show that upstream stimulatory factor 1 (USF1) and USF2 bind to the E box and regulate ␤ 2 m transactivation. The nuclear factor B (NF-B) subunits p50 and p65 bind to the B box and p65 transactivates ␤ 2 m. Interferon regulatory factor 1 (IRF1) , Introduction␤ 2 -Microglobulin (␤ 2 m) is a ubiquitously expressed 12-kDa glycoprotein that associates with major histocompatibility complex (MHC) class I (-like) molecules that are of great importance in antigen presentation, IgG transport, and iron metabolism. 1 As such, ␤ 2 m is linked to a variety of human diseases because of its association with immunologically and hematologically relevant molecules. ␤ 2 m is best known for its association with the MHC class I heavy chain, which is essential for the stable expression of these antigen-presenting molecules. Classical MHC class I molecules (HLA-A, -B, and -C) are ubiquitously expressed in most somatic cells. They are essential in the immune response because they present antigen-derived peptides to cytotoxic T lymphocytes and are important in protection against natural killer (NK) cellmediated cytotoxicity. 2 ␤ 2 m also associates with MHC class Ib or class I-like molecules, such as HLA-E, -F, -G, and CD1, which have a more restricted tissue distribution and have more specialized functions in antigen presentation. 3-5 ␤ 2 m is also a partner of HFE (formerly called HLA-H), an MHC class I-like molecule that is important for transferrin-mediated iron uptake. [6][7][8][9] Patients suffering from hereditary hemochromatosis have been found to bear a mutation in the HFE gene that specifically disrupts its association with ␤ 2 m, resulting in a strongly compromised function. 6,7 This is characterized by iron accumulation in parenchymal cells in various organs but a paucity of iron in Kupffer cells and macrophages. [6][7][8][9] Clinical consequences include liver cirrhosis, diabetes, arthritis, and heart failure. Furthermore, ␤ 2 m is also able to form a dimer with the neonatal Fc receptor, which is important for fetomaternal transport of IgG. 10,11 Finally, a role for ␤ 2 m has also been suggested in amyloidosis. Patients undergoing long-term dialysis often develop amyloidosis, which in turn affects bone cell metabolism by inducing bone mineral dissolving and enhancing osteoblast proliferation. 12,13 This is thought to be related to the binding of ␤ 2 m with ␣ 2 -macroglobulin and heparin sulfate. 14,15 Because ␤ 2 m is essential for the functioning of molecules central i...

A 5′ Extended IFN-Stimulating Response Element Is Crucial for IFN-γ–Induced Tripartite Motif 22 Expression via Interaction with IFN Regulatory Factor-1

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Fluorescence resonance energy transfer in near-infrared fluorescent oligonucleotide probes for detecting protein–DNA interactions

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