The process of nuclear protein transport requires the interaction of several different proteins, either directly or indirectly with nuclear localization or targeting sequences (NLS). Recently, a number of karyopherins ␣, or NLS-binding proteins, have been identified. We have found that the karyopherins hSRP1 and hSRP1␣ are differentially expressed in various leukocyte cell lines and could be induced in normal human peripheral blood lymphocytes. We show that the two karyopherins bind with varied specificities in a sequence specific manner to different NLSs and that the sequence specificity is modulated by other cytosolic proteins. There was a correlation between binding of karyopherins ␣ to different NLSs and their ability to be imported into the nucleus. Taken together, these data provide evidence for multiple levels of control of the nuclear import process.Active nuclear transport of proteins with molecular weights greater than 40 -60 kDa requires at least four different proteins, which act in a sequential manner with karyophilic proteins containing nuclear localization targeting sequences (NLS) 1 (1-4). There appear to be several discrete steps in the import process which involves: 1) binding of the NLS-binding protein, karyopherin ␣, to an NLS; 2) interaction of this complex with karyopherin ; 3) targeting to nuclear pore proteins; and 4) the ATP/GTP-dependent translocation through the nuclear pore mediated by ran (1,5,6).Recently, the proteins involved in NLS binding and transport have been identified. Those proteins that interact directly with the NLS have been termed karyopherins ␣ (7-11). The Xenopus protein importin 60 was the first karyopherin ␣ to be cloned, sequenced, and shown to be involved in nuclear protein import (7). Subsequently, a number of other karyopherins ␣ have been identified, which suggests that there is a family of these NLS-binding proteins. The two major groups of karyopherins ␣ include 1) the yeast protein SRP1 (12) and the human proteins hSRP1 and NPI-1 (8, 9), and 2) importin 60 (7) and the human proteins hSRP1␣ (11) and Rch1 (10). In this report we have termed hSRP1 and hSRP1␣, K1 and K2, respectively. Each of these karyopherins ␣ are capable of binding to NLSs and facilitating nuclear import. Recently it was shown that there was tissue-specific expression of the mouse K1 (mSRP1) and K2 (mPendulin). The levels of K1 RNA appear higher in the brain and cerebellum, whereas K2 RNA was found mostly in the thymus and spleen (13).Similar to karyopherin ␣, there are several homologs of karyopherin , (also called importin 90 or p97) (11,14). The function of karyopherin  appears to be the targeting of the karyophile-karyopherin ␣ complex to the nuclear pore (11,16). The interaction of karyopherin  with karyopherin ␣ has been shown to enhance the latter protein's affinity for the NLS containing protein (1). Although the protein factors described above are sufficient to support nuclear protein transport, there are accessory factors which are also important for regulating nuclear transp...
CD28 and CTLA-4, T cell receptors for B7-1 (CD80) and B7-2 (CD86) molecules on antigen-presenting cells, transmit costimulatory signals important for optimal T cell activation. Despite sharing sequence homology and common ligands, these receptors have distinct binding properties and patterns of expression. The function of CTLA-4 during T cell activation is not well understood, although an important role is suggested by complete amino acid sequence conservation of its cytoplasmic tail in all species studied to date. We report here a role of the cytoplasmic tail of CTLA-4 in regulating its subcellular localization and cell surface expression. In activated human peripheral blood T cells, or in several transfected or transduced cell types, CTLA-4 is not primarily a cell surface protein, but rather is localized intracellularly in a region which overlaps the Golgi apparatus.
The transcription factor NF-κB regulates many genes involved in proinflammatory and immune responses. The transport of NF-κB into the nucleus is essential for its biologic activity. We describe a novel, potent, and selective NF-κB inhibitor composed of a cell-permeable peptide carrying two nuclear localization sequences (NLS). This peptide blocks NF-κB nuclear localization, resulting in inhibition of cell surface protein expression, cytokine production, and T cell proliferation. The peptide is efficacious in vivo in a mouse septic shock model as well as a mouse model of inflammatory bowel disease, demonstrating that NF-κB nuclear import plays a role in these acute inflammatory disease models.
The effect of interferon-gamma (IFN-gamma) on the ability of human monocytic cells to process exogenous (major histocompability complex class II) antigens was investigated. The processing (i.e. protein degradation) of antigens that were internalized via Fc gamma receptor (Fc gamma R) was followed for various times after treatment of cells with IFN-gamma. THP-1 cells that had been treated with IFN-gamma for 4 h degraded antigen, internalized as an immune complex, at an enhanced rate. After 24 h of IFN-gamma treatment the rate of processing was similar to untreated cells. Unexpectedly, in cells which had been treated for 48-72 h there was a significant decrease in the rate of processing of the exogenous antigen. These effects were not due to changes in the rate of internalization of immune complex. The inhibition of the rate of processing was independent of the type of antigen, was dependent on the dose of IFN-gamma, and also occurred with normal human peripheral monocytes. Analysis of the degraded peptides by high-pressure liquid chromatography indicated that some of the peptides generated in the IFN-gamma-treated cells were both quantitatively and qualitatively different from the peptides generated in untreated cells. These data suggest that IFN-gamma modulates the way in which antigens, internalized through Fc receptors as immune complexes, are processed. Additionally, the results imply that decreases in the rate of antigen processing may lead to more efficient antigen presentation.
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