Structure and function of major histocompatibility complex class I antigens.
ABSTRACT Major histocompatibility complex (MHC) class I molecules control the repertoire and function of CD8 T cells and NK cells, and both cell types are involved in transplant rejection. Understanding the regulatory role of MHC class I molecules is important in the design of better therapies. This review article focuses on molecular aspects of alloreactive recognition of MHC class I molecules by CD8 T cells and NK cells and on the functional activities of CD8 T cells and NK cells in transplant rejection and tolerance.
Recent T cell receptor (TCR)-peptide-MHC class I crystal structures and structural and functional analyses of MHC class I interactions with NK cell inhibitory receptors have revealed new insights into molecular aspects of allorecognition of MHC class I molecules by CD8 T cells and NK cells. In functional studies, CD8 T cells and NK cells have been shown to have conditional and model-dependent roles in allograft rejection. NK cells have also been shown to have an unexpected role in tolerance induction in the transplantation setting.
Both CD8 and NK cells play diverse roles in graft rejection and tolerance induction. Further understanding of molecular interactions between MHC class I molecules and TCRs or NK receptors is important and highly relevant to transplantation.
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ABSTRACT: HERC2 is a large E3 ubiquitin ligase with multiple structural domains that has been implicated in an array of cellular processes. Mutations in HERC2 are linked to developmental delays and impairment caused by nervous system dysfunction, such as Angelman Syndrome and autism-spectrum disorders. However, HERC2 cellular activity and regulation remains poorly understood. We used a broad proteomic approach to survey the landscape of cellular proteins that interact with HERC2. We identified nearly three hundred potential interactors, a subset of which we validated binding to HERC2. The potential HERC2 interactors included the eukaryotic translation initiation factor 3 complex, the intracellular transport COPI coatomer complex, the glycogen regulator phosphorylase kinase, beta-catenin, PI3 kinase and proteins involved in fatty acid transport and iron homeostasis. Through a complex bioinformatic analysis of potential interactors, we linked HERC2 to cellular processes including intracellular protein trafficking and transport, metabolism of cellular energy, and protein translation. Given its size, multi-domain structure and association with various cellular activities, HERC2 may function as a scaffold to integrate protein complexes and bridge critical cellular pathways. This work provides a significant resource with which to interrogate HERC2 function more deeply and evaluate its contributions to mechanisms governing cellular homeostasis and disease.Journal of Proteome Research 12/2014; 14(2). · 5.06 Impact Factor
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ABSTRACT: Endoplasmic reticulum (ER) chaperones and oxidoreductases are abundant enzymes that mediate the production of fully folded secretory and transmembrane proteins. Resisting the Golgi and plasma membrane-directed "bulk flow," ER chaperones and oxidoreductases enter retrograde trafficking whenever they are pulled outside of the ER by their substrates. Solid tumors are characterized by the increased production of reactive oxygen species (ROS), combined with reduced blood flow that leads to low oxygen supply and ER stress. Under these conditions, hypoxia and the unfolded protein response upregulate their target genes. When this occurs, ER oxidoreductases and chaperones become important regulators of tumor growth. However, under these conditions, these proteins not only promote the folding of proteins, but also alter the properties of the plasma membrane and hence modulate tumor immune recognition. For instance, high levels of calreticulin serve as an "eat-me" signal on the surface of tumor cells. Conversely, both intracellular and surface BiP/GRP78 promotes tumor growth. Other ER folding assistants able to modulate the properties of tumor tissue include protein disulfide isomerase (PDI), Ero1α and GRP94. Understanding the roles and mechanisms of ER chaperones in regulating tumor cell functions and immunorecognition will lead to important insight for the development of novel cancer therapies.Frontiers in oncology. 01/2014; 4:291.
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ABSTRACT: The human major histocompatibility complex is a multi-gene ∼4Mb of DNA including the highly polymorphic HLA genes which are fundamental in effecting a healthy immune response. Detailed knowledge of the structure and function of HLA genes and their alleles and HLA proteins and their allotypes has rapidly evolved because of their role in clinical transplantation. A significant additional finding is the association or linkage of a wide range of diseases with HLA. We review the function of HLA and the history of disease association studies and focus on specific informative examples in the context of recent genome-wide screening analyses.Molecular Immunology 10/2012; · 3.00 Impact Factor