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Gene Review

PSMB8  -  proteasome (prosome, macropain) subunit,...

Homo sapiens

Synonyms: ALDD, D6S216, D6S216E, JMP, LMP7, ...
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Disease relevance of PSMB8


Psychiatry related information on PSMB8

  • The Y2 receptor has been demonstrated to be the most predominant receptor subtype in the human brain and appears to be involved in many neuropeptide Y actions, such as the regulation of locomotor activity, cardiovascular functions, memory processing, circadian rhythms and release of other neurotransmitters [6].

High impact information on PSMB8

  • A subset of the proteasome beta-subunits (LMP2, LMP7, and MECL-1) and one of the accessory complexes, PA28, are upregulated by gamma-interferon and affect the generation of peptides to promote more efficient antigen recognition [7].
  • Two beta-subunits of the proteasome, LMP2 and LMP7, are inducible by interferon-gamma and alter the catalytic activities of this particle, enhancing the presentation of at least some antigens [8].
  • These results therefore dispute the hypothetical involvement of proteasomes in antigen processing, although a more subtle effect of LMP2 and LMP7 cannot be ruled out [9].
  • Transfection experiments showed that the substitution of beta5i (LMP7) for beta5 is necessary and sufficient for producing the peptide, whereas a mutated form of beta5i (LMP7) lacking the catalytically active site was ineffective [10].
  • Interferon (IFN) gamma induces replacements of the proteasomal subunits X and Y by LMP7 and LMP2, respectively, resulting in an alteration of the proteolytic specificity [11].

Chemical compound and disease context of PSMB8

  • Presentation of the C-terminal ILKEPVHGV epitope is impaired in ME275 melanoma cells by treatment with lactacystin, and is independent of expression of the IFN-gamma-inducible proteasome beta subunits LMP2 and LMP7 [12].
  • Variations in peptide YY and Y2 receptor genes are associated with severe obesity in Pima Indian men [13].
  • Neonatal exposure to hyperoxia resulted in development of retinal neovascularization that was prevented in Y2(-1-) -mice, and significantly inhibited in rats treated with the Y2-receptor antisense oligonucleotide [14].

Biological context of PSMB8

  • The products of the Lmp2 and Lmp7 genes located in the major histocompatibility complex (MHC) class II region are postulated to form part of the proteasome complex [15].
  • Delineation of the subunit composition of human proteasomes using antisera against the major histocompatibility complex-encoded LMP2 and LMP7 subunits [15].
  • Cleavage of the E4416-424Y peptide was not affected by treatment of the BL cells with IFN-gamma despite both significant up-regulation of Lmp2 and Lmp7 and reconstitution of chymotrypsin and trypsin-like activities against fluorogenic substrates to LCL-like levels [16].
  • Down-regulation of Lmp2 and Lmp7 and decreased chymotrypsin- and trypsin-like activities were also observed in purified proteasomes from a c-myc-transfected subline of the ER/EB2-5 LCL that has adopted a BL-like phenotype [16].
  • Upregulation of LMP2, but not LMP7, gene expression showed a close correlation with the changes in antibody reactivities observed upon bacterial invasion [17].

Anatomical context of PSMB8

  • Low expression of the IFN-gamma-regulated beta low molecular mass polypeptide (Lmp)2, Lmp7, and MECL-1 was demonstrated in a panel of seven BL lines that express the germinal center cell phenotype of the original tumor [16].
  • In contrast, LMP7 and TAP2 genes were expressed in these cell lines [18].
  • The results demonstrate that, in normal glands, thyrocytes and pancreatic islet cells express comparable moderate to low levels of LMP2 and LMP7 [19].
  • Control of LMP7 expression in human endothelial cells by cytokines regulating cellular and humoral immunity [20].
  • The findings indicate that regulation of levels of LMP7 is similar to and may be coupled with that of other molecules required for MHC class I-dependent immunity, and depends primarily on cytokines released by Th(1)helper lymphocytes [20].

Associations of PSMB8 with chemical compounds

  • These results suggest that NPY activates three receptor subtypes, a Y2 subtype possibly by a direct action on the smooth muscle cells, as well as a Y4 and a Y5 (or 'Y5-like') subtype which, respectively, release acetylcholine and an unknown neurotransmitter [21].
  • Analysis of Lmp7 mRNA and protein in paraformaldehyde-fixed placentas by in situ hybridization and immunohistochemistry revealed that both HLA class I-positive and HLA class I-negative trophoblast cells contain Lmp7 gene products [22].
  • Utilizing biotinylated-epoxomicin as a molecular probe, we demonstrate that epoxomicin covalently binds to the LMP7, X, MECL1, and Z catalytic subunits of the proteasome [23].
  • Using immunohistochemical and in situ hybridization methodologies the localization of neuropeptide tyrosine (NPY) and two of its receptors, the Y1- and the Y2-receptor (R), has been analysed in various tissues in normal animals and animals subjected to different experimental procedures as well as animals with a genetic and an acquired disease [24].
  • These findings demonstrate two main points: 1) LMP7 incorporation into the proteasome is of greater importance for the generation of the influenza A2 Matrix epitope than the presence of the LMP7's catalytic site; and 2) the interplay between cytosolic proteases and stability of target proteins is of importance in optimization of Ag presentation [25].

Physical interactions of PSMB8


Regulatory relationships of PSMB8

  • IL-10 downregulated IFN-gamma-induced increases in LMP7 levels, as did IL-12 [20].
  • We typed 285 IDDM patients and 337 HLA-DRB1-DQA1-DQB1 genotypically matched control subjects from an ethnically homogeneous population for both the G/T polymorphism in intron 6 of the LMP7 gene and the Arg-His polymorphism in the LMP2 gene [27].

Other interactions of PSMB8

  • Some human tumor cells exhibit deficient expression of the peptide transporters TAP1 and TAP2 and of the proteasome subunits low molecular weight protein (LMP)-2 and LMP-7, which could be partially restored by cytokine treatment [28].
  • A family-based association method revealed biased transmission of specific alleles from heterozygous parents to affected offspring for the TAP1 gene, as well as for the closely linked LMP2 and LMP7 genes encoding subunits of the immunoproteasome [29].
  • These proteins contain an active site of proteolysis, and LMP7 replaces PSMB5 as a component of the 20S proteasome after stimulation of cells by interferon-gamma [30].
  • Two major mechanisms in colorectal cancer appear to be responsible for the total loss of MHC surface expression (beta2m mutations and LMP7/TAP2 downregulation) that may contribute to the failure of T lymphocyte recognition during an immune response [31].
  • In this tissue, mRNA of Y2 and Y4 NPY receptor subtypes were highly expressed, whereas Y5 mRNA levels were very low and Y1 mRNA levels were intermediate [21].

Analytical, diagnostic and therapeutic context of PSMB8

  • RESULTS: In the case control study, no difference in allele or genotype frequency was seen between patients and control subjects at the LMP7 locus [1].
  • Western blot analysis of anti-proteasome precipitates demonstrated that the LMP7 protein is incorporated into the proteasome but has a molecular mass of 23 kDa, 7 kDa smaller than expected fro the derived protein sequence of either of the cDNA [32].
  • Immunoprecipitation of proteasomes and analysis on two-dimensional gels revealed that during maturation the inducible proteasome subunits LMP2, LMP7, and MECL-1 are up-regulated and that the neosynthesis of proteasomes is switched exclusively to the production of immunoproteasomes containing these subunits [33].
  • Consistent with these results, northern blot hybridization studies showed that HLA class I-positive (JEG-3) and HLA null (Jar) trophoblast-derived cell lines contain Lmp7 mRNA [22].
  • The relative expression of six proteosome subunits (existing subunits X, Y, and Z and immunoproteosome subunits LMP7, LMP2, and MECL1) in 54 RCCs was investigated using RT-PCR analysis and was compared with clinicopathological measures, including patient outcome [34].


  1. Association of the large multifunctional proteasome (LMP2) gene with Graves' disease is a result of linkage disequilibrium with the HLA haplotype DRB1*0304-DQB1*02-DQA1*0501. Heward, J.M., Allahabadia, A., Sheppard, M.C., Barnett, A.H., Franklyn, J.A., Gough, S.C. Clin. Endocrinol. (Oxf) (1999) [Pubmed]
  2. Loss of interferon-gamma inducibility of TAP1 and LMP2 in a renal cell carcinoma cell line. Dovhey, S.E., Ghosh, N.S., Wright, K.L. Cancer Res. (2000) [Pubmed]
  3. Down-regulation of HLA class I antigen-processing molecules in malignant melanoma: association with disease progression. Kageshita, T., Hirai, S., Ono, T., Hicklin, D.J., Ferrone, S. Am. J. Pathol. (1999) [Pubmed]
  4. Variations in proteasome subunit composition and enzymatic activity in B-lymphoma lines and normal B cells. Frisan, T., Levitsky, V., Masucci, M.G. Int. J. Cancer (2000) [Pubmed]
  5. Down-regulation of HLA class I antigen processing molecules: an immune escape mechanism of renal cell carcinoma? Atkins, D., Ferrone, S., Schmahl, G.E., Störkel, S., Seliger, B. J. Urol. (2004) [Pubmed]
  6. Regional distribution of neuropeptide Y Y2 receptor messenger RNA in the human post mortem brain. Caberlotto, L., Fuxe, K., Rimland, J.M., Sedvall, G., Hurd, Y.L. Neuroscience (1998) [Pubmed]
  7. Mechanisms of MHC class I--restricted antigen processing. Pamer, E., Cresswell, P. Annu. Rev. Immunol. (1998) [Pubmed]
  8. Antigen processing and presentation by the class I major histocompatibility complex. York, I.A., Rock, K.L. Annu. Rev. Immunol. (1996) [Pubmed]
  9. Proteasome subunits encoded in the MHC are not generally required for the processing of peptides bound by MHC class I molecules. Arnold, D., Driscoll, J., Androlewicz, M., Hughes, E., Cresswell, P., Spies, T. Nature (1992) [Pubmed]
  10. The production of a new MAGE-3 peptide presented to cytolytic T lymphocytes by HLA-B40 requires the immunoproteasome. Schultz, E.S., Chapiro, J., Lurquin, C., Claverol, S., Burlet-Schiltz, O., Warnier, G., Russo, V., Morel, S., Lévy, F., Boon, T., Van den Eynde, B.J., van der Bruggen, P. J. Exp. Med. (2002) [Pubmed]
  11. Newly identified pair of proteasomal subunits regulated reciprocally by interferon gamma. Hisamatsu, H., Shimbara, N., Saito, Y., Kristensen, P., Hendil, K.B., Fujiwara, T., Takahashi, E., Tanahashi, N., Tamura, T., Ichihara, A., Tanaka, K. J. Exp. Med. (1996) [Pubmed]
  12. IFN-gamma exposes a cryptic cytotoxic T lymphocyte epitope in HIV-1 reverse transcriptase. Sewell, A.K., Price, D.A., Teisserenc, H., Booth, B.L., Gileadi, U., Flavin, F.M., Trowsdale, J., Phillips, R.E., Cerundolo, V. J. Immunol. (1999) [Pubmed]
  13. Variations in peptide YY and Y2 receptor genes are associated with severe obesity in Pima Indian men. Ma, L., Tataranni, P.A., Hanson, R.L., Infante, A.M., Kobes, S., Bogardus, C., Baier, L.J. Diabetes (2005) [Pubmed]
  14. Neuropeptide Y and Y2-receptor are involved in development of diabetic retinopathy and retinal neovascularization. Koulu, M., Movafagh, S., Tuohimaa, J., Jaakkola, U., Kallio, J., Pesonen, U., Geng, Y., Karvonen, M.K., Vainio-Jylhä, E., Pöllönen, M., Kaipio-Salmi, K., Seppälä, H., Lee, E.W., Higgins, R.D., Zukowska, Z. Ann. Med. (2004) [Pubmed]
  15. Delineation of the subunit composition of human proteasomes using antisera against the major histocompatibility complex-encoded LMP2 and LMP7 subunits. Patel, S.D., Monaco, J.J., McDevitt, H.O. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  16. Phenotype-dependent differences in proteasome subunit composition and cleavage specificity in B cell lines. Frisan, T., Levitsky, V., Polack, A., Masucci, M.G. J. Immunol. (1998) [Pubmed]
  17. Invasion by Salmonella typhimurium induces increased expression of the LMP, MECL, and PA28 proteasome genes and changes in the peptide repertoire of HLA-B27. Maksymowych, W.P., Ikawa, T., Yamaguchi, A., Ikeda, M., McDonald, D., Laouar, L., Lahesmaa, R., Tamura, N., Khuong, A., Yu, D.T., Kane, K.P. Infect. Immun. (1998) [Pubmed]
  18. Molecular basis for lack of expression of HLA class I antigens in human small-cell lung carcinoma cell lines. Singal, D.P., Ye, M., Qiu, X. Int. J. Cancer (1996) [Pubmed]
  19. Proteasome subunits, low-molecular-mass polypeptides 2 and 7 are hyperexpressed by target cells in autoimmune thyroid disease but not in insulin-dependent diabetes mellitus: implications for autoimmunity. Vives-Pi, M., Vargas, F., James, R.F., Trowsdale, J., Costa, M., Sospedra, M., Somoza, N., Obiols, G., Tampé, R., Pujol-Borrell, R. Tissue Antigens (1997) [Pubmed]
  20. Control of LMP7 expression in human endothelial cells by cytokines regulating cellular and humoral immunity. Loukissa, A., Cardozo, C., Altschuller-Felberg, C., Nelson, J.E. Cytokine (2000) [Pubmed]
  21. NPY receptor subtypes involved in the contraction of the proximal colon of the rat. Félétou, M., Rodriguez, M., Beauverger, P., Germain, M., Imbert, J., Dromaint, S., Macia, C., Bourrienne, A., Henlin, J.M., Nicolas, J.P., Boutin, J.A., Galizzi, J.P., Fauchère, J.L., Canet, E., Duhault, J. Regul. Pept. (1998) [Pubmed]
  22. Cellular distribution of proteasome subunit Lmp7 mRNA and protein in human placentas. Roby, K.F., Yang, Y., Gershon, D., Hunt, J.S. Immunology (1995) [Pubmed]
  23. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Meng, L., Mohan, R., Kwok, B.H., Elofsson, M., Sin, N., Crews, C.M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  24. Neuropeptide Y: some viewpoints on a multifaceted peptide in the normal and diseased nervous system. Hökfelt, T., Broberger, C., Zhang, X., Diez, M., Kopp, J., Xu, Z., Landry, M., Bao, L., Schalling, M., Koistinaho, J., DeArmond, S.J., Prusiner, S., Gong, J., Walsh, J.H. Brain Res. Brain Res. Rev. (1998) [Pubmed]
  25. Generation of an immunodominant CTL epitope is affected by proteasome subunit composition and stability of the antigenic protein. Gileadi, U., Moins-Teisserenc, H.T., Correa, I., Booth, B.L., Dunbar, P.R., Sewell, A.K., Trowsdale, J., Phillips, R.E., Cerundolo, V. J. Immunol. (1999) [Pubmed]
  26. Characterization of the neuropeptide Y5 receptor in the human hypothalamus: a lack of correlation between Y5 mRNA levels and binding sites. Statnick, M.A., Schober, D.A., Gackenheimer, S., Johnson, D., Beavers, L., Mayne, N.G., Burnett, J.P., Gadski, R., Gehlert, D.R. Brain Res. (1998) [Pubmed]
  27. No independent associations of LMP2 and LMP7 polymorphisms with susceptibility to develop IDDM. Undlien, D.E., Akselsen, H.E., Joner, G., Dahl-Jørgensen, K., Søvik, O., Rønningen, K.S., Thorsby, E. Diabetes (1997) [Pubmed]
  28. IFN-gamma-mediated coordinated transcriptional regulation of the human TAP-1 and LMP-2 genes in human renal cell carcinoma. Seliger, B., Hammers, S., Höhne, A., Zeidler, R., Knuth, A., Gerharz, C.D., Huber, C. Clin. Cancer Res. (1997) [Pubmed]
  29. Genes of the LMP/TAP cluster are associated with the human autoimmune disease vitiligo. Casp, C.B., She, J.X., McCormack, W.T. Genes Immun. (2003) [Pubmed]
  30. Natural selection during functional divergence to LMP7 and proteasome subunit X (PSMB5) following gene duplication. Bos, D.H. J. Mol. Evol. (2005) [Pubmed]
  31. Total loss of MHC class I in colorectal tumors can be explained by two molecular pathways: beta2-microglobulin inactivation in MSI-positive tumors and LMP7/TAP2 downregulation in MSI-negative tumors. Cabrera, C.M., Jiménez, P., Cabrera, T., Esparza, C., Ruiz-Cabello, F., Garrido, F. Tissue Antigens (2003) [Pubmed]
  32. The major histocompatibility complex-encoded proteasome component LMP7: alternative first exons and post-translational processing. Glynne, R., Kerr, L.A., Mockridge, I., Beck, S., Kelly, A., Trowsdale, J. Eur. J. Immunol. (1993) [Pubmed]
  33. Dendritic cells up-regulate immunoproteasomes and the proteasome regulator PA28 during maturation. Macagno, A., Gilliet, M., Sallusto, F., Lanzavecchia, A., Nestle, F.O., Groettrup, M. Eur. J. Immunol. (1999) [Pubmed]
  34. Prognostic significance of immuno-proteosome subunit expression in patients with renal-cell carcinoma: a preliminary study. Murakami, Y., Kanda, K., Yokota, K., Kanayama, H., Kagawa, S. Molecular urology. (2001) [Pubmed]
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