The major histocompatibility complex class I heavy chain as a structural subunit of the human cell membrane insulin receptor: implications for the range of biological functions of histocompatibility antigens.

Due, Claus; Simonsen, Morten; Olsson, Lennart

doi:10.1073/pnas.83.16.6007

Cited by 132 publications

(58 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We cannot distinguish between these possibilities, but the accumulated evidence indicates that the cis association and the open MHC I conformers are interdependent events. In this regard, the presence of open MHC I conformers was obligatory for cis association with the insulin receptor to occur, and the cis association was blocked after the exogenous addition of b2m (50,51). The novel cis association that we report in this article may have some implications for the MHC I A splice variant in the fine tuning of classical MHC I A/ TCR and MHC I A/KIR interactions.…”

Section: Discussionmentioning

confidence: 70%

The β2-Microglobulin–Free Heterodimerization of Rhesus Monkey MHC Class I A with Its Normally Spliced Variant Reduces the Ubiquitin-Dependent Degradation of MHC Class I A

Dai

Zhang

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

The MHC class I (MHC I) molecules play a pivotal role in the regulation of immune responses by presenting antigenic peptides to CTLs and by regulating cytolytic activities of NK cells. In this article, we show that MHC I A in rhesus macaques can be alternatively spliced, generating a novel MHC I A isoform (termed “MHC I A-sv1”) devoid of α3 domain. Despite the absence of β2-microglobulin (β2m), the MHC I A-sv1 proteins reached the cell surface of K562-transfected cells as endoglycosidase H-sensitive glycoproteins that could form disulfide-bonded homodimers. Cycloheximide-based protein chase experiments showed that the MHC I A-sv1 proteins were more stable than the full-length MHC I A in transiently or stably transfected cell lines. Of particular interest, our studies demonstrated that MHC I A-sv1 could form β2m-free heterodimers with its full-length protein in mammalian cells. The formation of heterodimers was accompanied by a reduction in full-length MHC I A ubiquitination and consequent stabilization of the protein. Taken together, these results demonstrated that MHC I A-sv1 and MHC I A can form a novel heterodimeric complex as a result of the displacement of β2m and illustrated the relevance of regulated MHC I A protein degradation in the β2m-free heterodimerization-dependent control, which may have some implications for the MHC I A splice variant in the fine tuning of classical MHC I A/TCR and MHC I A/killer cell Ig-like receptor interactions.

show abstract

Section: Discussionmentioning

confidence: 70%

The β2-Microglobulin–Free Heterodimerization of Rhesus Monkey MHC Class I A with Its Normally Spliced Variant Reduces the Ubiquitin-Dependent Degradation of MHC Class I A

Dai

Zhang

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…HLA/IR associate in membranes of lymphocytes, adipocytes, and hepatoma cells (Due et al, 1986;Samson et al, 1986;Cousin et al, 1987;Olsson et al, 1994;Shibata et al, 1995). Our studies have characterized the association and its consequences in B-lymphoblasts, cells that respond to physiological concentrations of insulin (Helderman, 1983;Snow, 1985;Valentine et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Interaction of Class I Human Leukocyte Antigen (HLA-I) Molecules with Insulin Receptors and Its Effect on the Insulin-Signaling Cascade

Ramalingam

Chakrabarti

Edidin

1997

MBoC

View full text Add to dashboard Cite

Insulin receptor (IR) and class I major histocompatibility complex molecules associate with one another in cell membranes, but the functional consequences of this association are not defined. We found that IR and human class I molecules (HLA-I) associate in liposome membranes and that the affinity of IR for insulin and its tyrosine kinase activity increase as the HLA:IR ratio increases over the range 1:1 to 20:1. The same relationship between HLA:IR and IR function was found in a series of B-LCL cell lines. The association of HLA-I and IR depends upon the presence of free HLA heavy chains. All of the effects noted were reduced or abrogated if liposomes or cells were incubated with excess HLA-I light chain, ␤2-microglobulin. Increasing HLA:IR also enhanced phosphorylation of insulin receptor substrate-1 and the activation of phosphoinositide 3-kinase. HLA-I molecules themselves were phosphorylated on tyrosine and associated with phosphoinositide 3-kinase when B-LCL were stimulated with insulin. INTRODUCTIONThe manifold effects of insulin on cell physiology are mediated by a specific insulin receptor (IR). Insulin binding triggers a conformational change in IR, stimulating its tyrosine kinase activity and leading to its autophosphorylation (Rosen, 1987;White and Kahn, 1994). The insulin signal is propagated downstream of the IR kinase by the binding and tyrosine phosphorylation of docking proteins that connect IR to signaling pathways by mediating the binding of intracellular signaling proteins (Backer et al., 1992;Kuhne et al., 1993;Myers et al., 1994).IR has been shown to associate with other proteins in the plane of the plasma membrane. Some of these associations, i.e., with PC-1, a transmembrane glycoprotein (Maddux et al., 1995) and with ␤ adrenergic receptors (Karoor, et al., 1995;Baltensperger, et al., 1996), clearly have functional consequences. The first affects the kinase activity of IR, and the second affects the function of ␤ adrenergic receptors. In contrast, no functional effects have been clearly shown for another lateral association of IR, i.e., that with the major histocompatibility complex (MHC) I molecules, mouse H2 and human HLA. Although the association of IR with these molecules has been demonstrated using biophysical and biochemical techniques (Fehlmann et al., 1985a;Phillips et al., 1986;Edidin and Reiland, 1990;Liegler et al., 1991), there is little evidence that this association has functional consequences for either IR or MHC I molecules. At best, some studies correlate MHC phenotype with insulin binding and signaling activity (Lafuse and Edidin, 1980;Kittur et al., 1987;Edidin, 1988), but others do not (Verland et al., 1989;Liegler et al., 1991). Thus the consequences, if any, of the association between IR and MHC I molecules remain unclear.We have used a two-part strategy to detect the formation of molecular complexes between IR and human MHC I molecules, HLA, and to measure the functional consequences of this association for insulinmediated signaling and the state of MHC phosphorylati...

show abstract

“…18,19 Even though many of these associations could be due to genes within the MHC locus, there also is evidence indicating that classical MHC antigens themselves may regulate physiological processes by interacting physically on the cell surface with different ligands. [20][21][22] HFE itself, a nonclassical MHC-I protein, was shown to interact with the transferrin receptor. 23 Recently, a study in ␤ 2 m Ϫ/Ϫ mice demonstrated that MHC-I molecules are functionally required for the development and plasticity of the central nervous system.…”

Section: Resultsmentioning

confidence: 99%

Increased hepatic iron in mice lacking classical MHC class I molecules

Cardoso

Macedo²,

Röhrlich³

et al. 2002

Blood

View full text Add to dashboard Cite

Iron accumulation in the liver in hereditary hemochromatosis (HH) has been shown to be highly variable. Some studies point to the importance of major histocompatibility complex (MHC) class I (MHC-I) and CD8 ؉ cells as modifiers of iron overload. In this report, using mice knockout for H2K b؊/؊ and H2D b؊/؊ genes, it is demonstrated that lack of classical MHC-I molecules results in a spontaneous increase of nonheme iron content in the liver (mainly located in the hepatocytes) when compared to wild-type mice. In CD8 ؊/؊ and Rag2 ؊/؊ mice, no spontaneous hepatic iron accumulation was ob- IntroductionSince the discovery of the HFE gene, 1 several molecules implicated in heritable defects of iron metabolism have been identified, giving new insights into the molecular control of cellular pathways of iron balance. 2 Despite these advances, a considerable unexplained variability in the amount of iron loading in HFE hemochromatosis still persists. 3,4 Thus, the finding of new molecular regulators to further improve our understanding of iron homeodynamics continues to be pertinent. Recently, Andrews and collaborators made an important contribution in this area by characterizing genes that modify the hemochromatosis phenotype in mice. They reported that mice double knockout for Hfe and ␤ 2 -microglobulin (␤ 2 m) accumulate more tissue iron than mice lacking Hfe only. 4 This finding suggests that other(s) ␤ 2 m-interacting protein(s), such as classical major histocompatibility complex (MHC) class I molecule(s) (MHC-I), may be involved in iron regulation. Alternatively, MHC-dependent cells such as CD8 ϩ T lymphocytes or others could play a role in iron metabolism. 5 To further explore other candidate molecular and cellular regulators of iron balance, we investigated the spontaneous iron status of mice with disrupted classical Mhc-I genes and of mice knockout for CD8 and Rag2 genes. Study designC57BL/6J (B6), H2K bϪ/Ϫ , H2D bϪ/Ϫ single-knockout and H2K bϪ/Ϫ D bϪ/Ϫ double-knockout mice were raised at the Pasteur Institute animal facilities and are reported elsewhere. 6 All H2 knockout mice were backcrossed onto the B6 background for 12 generations. The CD8 knockout mice (CD8␣ Ϫ/Ϫ ) 7 that had been backcrossed to B6 for 13 generations were purchased from The Jackson Laboratory (Bar Harbor, ME) at 8 to 9 weeks and aged at the Institute for Molecular and Cell Biology (IBMC) animal facility. Rag2 Ϫ/Ϫ8 were backcrossed 9 times onto the B6 background; additional B6 mice were bred in IBMC. All mice used in this study were male, aged 4 to 5 months, and were maintained on standard mouse diet. Iron status was evaluated as previously described. 9 Iron staining in the liver was performed by using the Perls Prussian blue method, and evaluation of ferritin accumulation was done by electron microscopy in liver samples processed as described. 10 The blood samples were obtained by cardiac puncture in mice under anesthesia or by retro-orbital bleeding. Serum transferrin saturation was calculated by dividing serum iron by total iron-binding cap...

show abstract

The major histocompatibility complex class I heavy chain as a structural subunit of the human cell membrane insulin receptor: implications for the range of biological functions of histocompatibility antigens.

Cited by 132 publications

References 34 publications

The β2-Microglobulin–Free Heterodimerization of Rhesus Monkey MHC Class I A with Its Normally Spliced Variant Reduces the Ubiquitin-Dependent Degradation of MHC Class I A

The β2-Microglobulin–Free Heterodimerization of Rhesus Monkey MHC Class I A with Its Normally Spliced Variant Reduces the Ubiquitin-Dependent Degradation of MHC Class I A

Interaction of Class I Human Leukocyte Antigen (HLA-I) Molecules with Insulin Receptors and Its Effect on the Insulin-Signaling Cascade

Increased hepatic iron in mice lacking classical MHC class I molecules

Contact Info

Product

Resources

About