Evolutionary and functional perspectives of the major histocompatibility complex class I antigen-processing machinery

Major histocompatibility complex (MHC) class I molecules present antigenic peptides to CD8+ T cells, providing the basis for immune recognition of pathogen-infected cells. Peptides generated mainly by proteasomes in the cytosol are transported into the lumen of the endoplasmic reticulum by transporters associated with antigen processing (TAP). The maturation of MHC class I molecules is controlled by a number of accessory proteins and chaperones that are to a varying degree dedicated to the assembly of MHC class I. Several newly characterised proteins have been demonstrated to play important roles in this process. This review focuses on the functional relationship and evolutionary history of the antigen-processing machinery (APM) components and MHC class I itself. These are of great interest for further elucidating the origin of the immune system and understanding the mechanisms of antigen presentation and immunology in general.     

Virus-immune T cells and the major histocompatibility complex: Evolution of some basic concepts over the past two years

Cellular and Molecular Life Sciences -     

The major OLA histocompatibility complex of sheep. Recent results in the genetic study of 11 factors previously defined by microlymphocytotoxicity]

The genetic study of 11 lymphocyte factors previously described in sheep was continued. 9 factors are the products of alleles at two closely linked loci OLA-A and B. The last two factors are the products of two genes at two distinct loci OL-X and OL-Z. Recombinations between the two closely linked loci are very rare (0.6%); but they are frequent between these two loci and OL-X (26%). The OL-Z locus seems to be independent of the two linked loci OLA-A and B. The allele frequencies at the four loci are given.     

Structure of victorin C,the major host-selective toxin fromCochliobolus victoriae

Summary The predominant host-selective toxin fromCochliobolus victoriae, victorin C, is a peptide with an apparent mol. wt of 796, representing a cyclic array of the subunits1–6. The structure of the toxin has now been established as in16 through analysis of the degradation products generated by enzymic and non-enzymic partial hydrolysis. The presence of a hydrated aldehydo group requires for victorin C the composition C₃₁H₄₅O₁₃N₆Cl₃ with an amended mol. wt of 814, for which independent experimental support has been secured.     

Isolation ofβ 2-microglobulin from the urine of patients with itai-itai (Ouch-ouch) disease

Zusammenfassung Im 24-h-Urin von Frauen mit der seltenen Itai-itai-Krankheit wurde das gleiche ₂-mikroglobulin nachgewiesen, das auch bei chronischer Cadmium-Intoxikation ausgeschieden wird.     

Regulation of the type III InsP3 receptor and its role in beta cell function

The type III inositol 1,4,5-trisphosphate receptor (InsP3R) is an important intracellular calcium (Ca2+) release channel in the pancreatic beta cell. Pancreatic beta cells secrete insulin following a characteristic change in membrane potential that leads to an increase in cytoplasmic Ca2+. Both extracellular Ca2+ and Ca2+ mobilized from InsP3-sensitive stores contribute to this increase. RIN-m5F cells, an insulin-secreting beta cell line, preferentially express the type III InsP3R. These cells have been useful in determining the regulatory properties of the type III InsP3R and the role of this isoform in an intact cell. The type III InsP3R is ideal for signal initiation because high cytoplasmic Ca2+ does not inhibit its activity. Altered insulin secretion, the result of changes in Ca2+ handling by the beta cell, has significant clinical consequences.     

The antioxidant function of Bcl-2 preserves cytoskeletal stability of cells with defective respiratory complex I

Human thyroid carcinoma XTC.UC1 cells harbor a homoplasmic frameshift mutation in the MT-ND1 subunit of respiratory complex I. When forced to use exclusively oxidative phosphorylation for energy production by inhibiting glycolysis, these cells triggered a caspase-independent cell death pathway, which was associated to a significant imbalance in glutathione homeostasis and a cleavage of the actin cytoskeleton. Overexpression of the anti-apoptotic Bcl-2 protein significantly increased the level of endogenous reduced glutathione, thus preventing its oxidation after the metabolic stress. Furthermore, Bcl-2 completely inhibited actin cleavage and increased cell adhesion, but was unable to improve cellular viability. Similar effects were obtained when XTC.UC1 cells were incubated with exogenous glutathione. We hence propose that Bcl-2 can safeguard cytoskeletal stability through an antioxidant function. Received 28 May 2008; received after revision 8 July 2008; accepted 29 July 2008     

Models and the dynamics of theory-building in physics. Part I—Modeling strategies

A deeper understanding of models is sought in considering what models do, rather what they are. This distinction emphasizes how two different modeling strategies, as they pursue different purposes, do invest in different options, in particular in regard to rigor and immediate empirical relevance. The analysis focuses therefore on the services expected from models by the scientists who construct them: models are sought for how they contribute to exploring and testing the context in which they operate. In a forthcoming Part II these general considerations will be anchored in the presentation of specific case studies.     

Morphometric study of the aortic body type I cell.

The subclavian glomus (aortic body) of New Zealand white rabbits was examined ultrastructurally using stereological morphometric analysis. The Type I cells of the glomus possess numerous electron-opaque vesicles which occupy approximately 12% of the cytoplasmic volume of the cells. The amine-containing vesicles comprise a heterogeneous population of vesicles with a mean caliper diameter of 113.5 nm. Differences in vesicle diameters may indicate the storage of different biogenic amines, different secretion or maturation states between glomera and/or additional physiological functions for the glomera.     

Structure and function of type I copper in multicopper oxidases

The type I copper center in multicopper oxidases is constructed from 1Cys2His and weakly coordinating 1Met or the non-coordinating 1Phe/1Leu, and it exhibits spectral properties and an alkaline transition similar to those of the blue copper center in blue copper proteins. Since the type I copper center in multicopper oxidases is deeply buried inside the protein molecule, electron transfers to and from type I copper are performed through specific pathways: the hydrogen bond between an amino acid located at the substrate binding site and a His residue coordinating type I copper, and the His-Cys-His sequence connecting the type I copper center and the trinuclear copper center comprised of a type II copper and a pair of type III coppers. The intramolecular electron transfer rates can be tuned by mutating the fourth ligand of type I copper. Further, mutation at the Cys ligand gives a vacant type I copper center and traps the reaction intermediate during the four-electron reduction of dioxygen.     

Electronmicroscopic identification of type C particles in cultured murine neuroblastoma

Summary Monolayer of murine neuroblastoma were treated with dexamethasone and examined by electronmicroscopy. Most of the treated cells were morphologically differentiated and exhibited type C virus particles which were budding from the cell surface. This in vitro system may be of great value for exploring the oncogenic potential of the virus, and its possible role in cell differentiation.Acknowledgments. The authors wish to thank Dr K.N. Prasad, Department of Radiology, University of Colorado Medical Center, for providing the NBP₂ clone, and Mr P. Reimann for photographic assistance. This research was supported in part by NIH Grant NS 11650 to T.H.W.     

Decreased levels of complex III core protein 1 and complex V beta chain in brains from patients with Alzheimer's disease and Down syndrome

Ubiquinol:cytochrome c oxidoreductase (complex III) and ATP synthase (complex V) are important enzymes in the mitochondrial electron transport chain. Defects in mitochondrial respiratory enzymes have been reported for several neurodegenerative diseases. In this study, we applied the proteomic approach to investigate protein levels of complex III core protein and complex V beta chain in brain regions of Alzheimer's disease (AD) and Down syndrome (DS) patients. Complex III core protein 1 was significantly reduced in the temporal cortex of AD patients. Complex V beta chain was significantly reduced in the frontal cortex of DS patients. We conclude that decreased mitochondrial respiratory enzymes could contribute to the impairment of energy metabolism observed in DS. These decreases could also cause the generation of reactive oxygen species and neuronal cell death (apoptosis) in DS as well as AD.     

Direct evidence that the N-terminal extensions of the TAP complex act as autonomous interaction scaffolds for the assembly of the MHC I peptide-loading complex

The loading of antigenic peptides onto major histocompatibility complex class I (MHC I) molecules is an essential step in the adaptive immune response against virally or malignantly transformed cells. The ER-resident peptide-loading complex (PLC) consists of the transporter associated with antigen processing (TAP1 and TAP2), assembled with the auxiliary factors tapasin and MHC I. Here, we demonstrated that the N-terminal extension of each TAP subunit represents an autonomous domain, named TMD(0), which is correctly targeted to and inserted into the ER membrane. In the absence of coreTAP, each TMD(0) recruits tapasin in a 1:1 stoichiometry. Although the TMD(0)s lack known ER retention/retrieval signals, they are localized to the ER membrane even in tapasin-deficient cells. We conclude that the TMD(0)s of TAP form autonomous interaction hubs linking antigen translocation into the ER with peptide loading onto MHC I, hence ensuring a major function in the integrity of the antigen-processing machinery.     

Electronmicroscopic identification of type C particles in cultured murine neuroblastoma.

Monolayer of murine neuroblastoma were treated with dexamethasone and examined by electronmicroscopy. Most of the treated cells were morphologically differentiated and exhibited type C virus particles which were budding from the cell surface. This in vitro system may be of great value for exploring the oncogenic potential of the virus, and its possible role in cell differentiation.     

Degradation of the mitochondrial complex I assembly factor TMEM126B under chronic hypoxia

Cell stress such as hypoxia elicits adaptive responses, also on the level of mitochondria, and in part is mediated by the hypoxia-inducible factor (HIF) 1α. Adaptation of mitochondria towards acute hypoxic conditions is reasonably well understood, while regulatory mechanisms, especially of respiratory chain assembly factors, under chronic hypoxia remains elusive. One of these assembly factors is transmembrane protein 126B (TMEM126B). This protein is part of the mitochondrial complex I assembly machinery. We identified changes in complex I abundance under chronic hypoxia, in association with impaired substrate-specific mitochondrial respiration. Complexome profiling of isolated mitochondria of the human leukemia monocytic cell line THP-1 revealed HIF-1α-dependent deficits in complex I assembly and mitochondrial complex I assembly complex (MCIA) abundance. Of all mitochondrial MCIA members, we proved a selective HIF-1-dependent decrease of TMEM126B under chronic hypoxia. Mechanistically, HIF-1α induces the E3-ubiquitin ligase F-box/WD repeat-containing protein 1A (β-TrCP1), which in turn facilitates the proteolytic degradation of TMEM126B. Attenuating a functional complex I assembly appears critical for cellular adaptation towards chronic hypoxia and is linked to destruction of the mitochondrial assembly factor TMEM126B.