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J Exp Med. 1996 April 1; 183(4): 1807–1816.
PMCID: PMC2192534

Newly identified pair of proteasomal subunits regulated reciprocally by interferon gamma


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. We found a third pair of proteasome subunits expressed reciprocally in response to IFN-gamma. Molecular cloning of a cDNA encoding one subunit designated as Z, downregulated by IFN-gamma, showed that it is a novel proteasomal subunit with high homology to MECL1, which is markedly induced by IFN-gamma. Thus, IFN- gamma induces subunit replacements of not only X and Y by LMP7 and LMP2, respectively, but also of Z by MECL1, producing proteasomes responsible for immunological processing of endogenous antigens. When processed from their precursors, three pairs of the 10 homologous, but distinct, beta-type subunits of eukaryotic proteasomes, that is, X/LMP7, Y/LMP2, and Z/MECL1, have an NH2-terminal threonine residue, assumed to be part of a catalytic center. These findings suggest that the altered molecular organization of the proteasome induced by IFN- gamma may be responsible for acquisition of its functional change.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Goldberg AL, Rock KL. Proteolysis, proteasomes and antigen presentation. Nature. 1992 Jun 4;357(6377):375–379. [PubMed]
  • Tanahashi N, Tsurumi C, Tamura T, Tanaka K. Molecular structure of 20S and 26S proteasomes. Enzyme Protein. 1993;47(4-6):241–251. [PubMed]
  • Peters JM, Cejka Z, Harris JR, Kleinschmidt JA, Baumeister W. Structural features of the 26 S proteasome complex. J Mol Biol. 1993 Dec 20;234(4):932–937. [PubMed]
  • Lupas A, Koster AJ, Baumeister W. Structural features of 26S and 20S proteasomes. Enzyme Protein. 1993;47(4-6):252–273. [PubMed]
  • Tanaka K. Molecular biology of proteasomes. Mol Biol Rep. 1995;21(1):21–26. [PubMed]
  • Peters JM. Proteasomes: protein degradation machines of the cell. Trends Biochem Sci. 1994 Sep;19(9):377–382. [PubMed]
  • Yoshimura T, Kameyama K, Takagi T, Ikai A, Tokunaga F, Koide T, Tanahashi N, Tamura T, Cejka Z, Baumeister W, et al. Molecular characterization of the "26S" proteasome complex from rat liver. J Struct Biol. 1993 Nov-Dec;111(3):200–211. [PubMed]
  • Rivett AJ. Proteasomes: multicatalytic proteinase complexes. Biochem J. 1993 Apr 1;291(Pt 1):1–10. [PubMed]
  • Goldberg AL. The mechanism and functions of ATP-dependent proteases in bacterial and animal cells. Eur J Biochem. 1992 Jan 15;203(1-2):9–23. [PubMed]
  • Rechsteiner M, Hoffman L, Dubiel W. The multicatalytic and 26 S proteases. J Biol Chem. 1993 Mar 25;268(9):6065–6068. [PubMed]
  • Hershko A, Ciechanover A. The ubiquitin system for protein degradation. Annu Rev Biochem. 1992;61:761–807. [PubMed]
  • Ciechanover A. The ubiquitin-proteasome proteolytic pathway. Cell. 1994 Oct 7;79(1):13–21. [PubMed]
  • Hochstrasser M. Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr Opin Cell Biol. 1995 Apr;7(2):215–223. [PubMed]
  • Murakami Y, Matsufuji S, Kameji T, Hayashi S, Igarashi K, Tamura T, Tanaka K, Ichihara A. Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature. 1992 Dec 10;360(6404):597–599. [PubMed]
  • Rock KL, Gramm C, Rothstein L, Clark K, Stein R, Dick L, Hwang D, Goldberg AL. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell. 1994 Sep 9;78(5):761–771. [PubMed]
  • Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994 Sep 9;78(5):773–785. [PubMed]
  • Michalek MT, Grant EP, Gramm C, Goldberg AL, Rock KL. A role for the ubiquitin-dependent proteolytic pathway in MHC class I-restricted antigen presentation. Nature. 1993 Jun 10;363(6429):552–554. [PubMed]
  • Heemels MT, Ploegh H. Generation, translocation, and presentation of MHC class I-restricted peptides. Annu Rev Biochem. 1995;64:463–491. [PubMed]
  • Driscoll J, Brown MG, Finley D, Monaco JJ. MHC-linked LMP gene products specifically alter peptidase activities of the proteasome. Nature. 1993 Sep 16;365(6443):262–264. [PubMed]
  • Gaczynska M, Rock KL, Goldberg AL. Gamma-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature. 1993 Sep 16;365(6443):264–267. [PubMed]
  • Aki M, Shimbara N, Takashina M, Akiyama K, Kagawa S, Tamura T, Tanahashi N, Yoshimura T, Tanaka K, Ichihara A. Interferon-gamma induces different subunit organizations and functional diversity of proteasomes. J Biochem. 1994 Feb;115(2):257–269. [PubMed]
  • Monaco JJ. A molecular model of MHC class-I-restricted antigen processing. Immunol Today. 1992 May;13(5):173–179. [PubMed]
  • Fehling HJ, Swat W, Laplace C, Kühn R, Rajewsky K, Müller U, von Boehmer H. MHC class I expression in mice lacking the proteasome subunit LMP-7. Science. 1994 Aug 26;265(5176):1234–1237. [PubMed]
  • Van Kaer L, Ashton-Rickardt PG, Eichelberger M, Gaczynska M, Nagashima K, Rock KL, Goldberg AL, Doherty PC, Tonegawa S. Altered peptidase and viral-specific T cell response in LMP2 mutant mice. Immunity. 1994 Oct;1(7):533–541. [PubMed]
  • Boes B, Hengel H, Ruppert T, Multhaup G, Koszinowski UH, Kloetzel PM. Interferon gamma stimulation modulates the proteolytic activity and cleavage site preference of 20S mouse proteasomes. J Exp Med. 1994 Mar 1;179(3):901–909. [PMC free article] [PubMed]
  • Früh K, Gossen M, Wang K, Bujard H, Peterson PA, Yang Y. Displacement of housekeeping proteasome subunits by MHC-encoded LMPs: a newly discovered mechanism for modulating the multicatalytic proteinase complex. EMBO J. 1994 Jul 15;13(14):3236–3244. [PubMed]
  • Akiyama K, Kagawa S, Tamura T, Shimbara N, Takashina M, Kristensen P, Hendil KB, Tanaka K, Ichihara A. Replacement of proteasome subunits X and Y by LMP7 and LMP2 induced by interferon-gamma for acquirement of the functional diversity responsible for antigen processing. FEBS Lett. 1994 Apr 18;343(1):85–88. [PubMed]
  • Akiyama K, Yokota K, Kagawa S, Shimbara N, Tamura T, Akioka H, Nothwang HG, Noda C, Tanaka K, Ichihara A. cDNA cloning and interferon gamma down-regulation of proteasomal subunits X and Y. Science. 1994 Aug 26;265(5176):1231–1234. [PubMed]
  • Belich MP, Glynne RJ, Senger G, Sheer D, Trowsdale J. Proteasome components with reciprocal expression to that of the MHC-encoded LMP proteins. Curr Biol. 1994 Sep 1;4(9):769–776. [PubMed]
  • Tanaka K. Role of proteasomes modified by interferon-gamma in antigen processing. J Leukoc Biol. 1994 Nov;56(5):571–575. [PubMed]
  • Arnold D, Driscoll J, Androlewicz M, Hughes E, Cresswell P, Spies T. Proteasome subunits encoded in the MHC are not generally required for the processing of peptides bound by MHC class I molecules. Nature. 1992 Nov 12;360(6400):171–174. [PubMed]
  • Momburg F, Ortiz-Navarrete V, Neefjes J, Goulmy E, van de Wal Y, Spits H, Powis SJ, Butcher GW, Howard JC, Walden P, et al. Proteasome subunits encoded by the major histocompatibility complex are not essential for antigen presentation. Nature. 1992 Nov 12;360(6400):174–177. [PubMed]
  • Yewdell J, Lapham C, Bacik I, Spies T, Bennink J. MHC-encoded proteasome subunits LMP2 and LMP7 are not required for efficient antigen presentation. J Immunol. 1994 Feb 1;152(3):1163–1170. [PubMed]
  • Zhou X, Momburg F, Liu T, Abdel Motal UM, Jondal M, Hämmerling GJ, Ljunggren HG. Presentation of viral antigens restricted by H-2Kb, Db or Kd in proteasome subunit LMP2- and LMP7-deficient cells. Eur J Immunol. 1994 Aug;24(8):1863–1868. [PubMed]
  • Lichter P, Ledbetter SA, Ledbetter DH, Ward DC. Fluorescence in situ hybridization with Alu and L1 polymerase chain reaction probes for rapid characterization of human chromosomes in hybrid cell lines. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6634–6638. [PubMed]
  • Takahashi E, Yamauchi M, Tsuji H, Hitomi A, Meuth M, Hori T. Chromosome mapping of the human cytidine-5'-triphosphate synthetase (CTPS) gene to band 1p34.1-p34.3 by fluorescence in situ hybridization. Hum Genet. 1991 Nov;88(1):119–121. [PubMed]
  • Kristensen P, Johnsen AH, Uerkvitz W, Tanaka K, Hendil KB. Human proteasome subunits from 2-dimensional gels identified by partial sequencing. Biochem Biophys Res Commun. 1994 Dec 30;205(3):1785–1789. [PubMed]
  • Larsen F, Solheim J, Kristensen T, Kolstø AB, Prydz H. A tight cluster of five unrelated human genes on chromosome 16q22.1. Hum Mol Genet. 1993 Oct;2(10):1589–1595. [PubMed]
  • Ustrell V, Pratt G, Rechsteiner M. Effects of interferon gamma and major histocompatibility complex-encoded subunits on peptidase activities of human multicatalytic proteases. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):584–588. [PubMed]
  • Kozak M. Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. Nucleic Acids Res. 1984 Jan 25;12(2):857–872. [PMC free article] [PubMed]
  • Zwickl P, Grziwa A, Pühler G, Dahlmann B, Lottspeich F, Baumeister W. Primary structure of the Thermoplasma proteasome and its implications for the structure, function, and evolution of the multicatalytic proteinase. Biochemistry. 1992 Feb 4;31(4):964–972. [PubMed]
  • Lee LW, Moomaw CR, Orth K, McGuire MJ, DeMartino GN, Slaughter CA. Relationships among the subunits of the high molecular weight proteinase, macropain (proteasome). Biochim Biophys Acta. 1990 Feb 9;1037(2):178–185. [PubMed]
  • Lilley KS, Davison MD, Rivett AJ. N-terminal sequence similarities between components of the multicatalytic proteinase complex. FEBS Lett. 1990 Mar 26;262(2):327–329. [PubMed]
  • Seemüller E, Lupas A, Stock D, Löwe J, Huber R, Baumeister W. Proteasome from Thermoplasma acidophilum: a threonine protease. Science. 1995 Apr 28;268(5210):579–582. [PubMed]
  • Fenteany G, Standaert RF, Lane WS, Choi S, Corey EJ, Schreiber SL. Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin. Science. 1995 May 5;268(5211):726–731. [PubMed]
  • Tamura T, Nagy I, Lupas A, Lottspeich F, Cejka Z, Schoofs G, Tanaka K, De Mot R, Baumeister W. The first characterization of a eubacterial proteasome: the 20S complex of Rhodococcus. Curr Biol. 1995 Jul 1;5(7):766–774. [PubMed]
  • Lupas A, Zwickl P, Baumeister W. Proteasome sequences in eubacteria. Trends Biochem Sci. 1994 Dec;19(12):533–534. [PubMed]
  • Heinemeyer W, Tröndle N, Albrecht G, Wolf DH. PRE5 and PRE6, the last missing genes encoding 20S proteasome subunits from yeast? Indication for a set of 14 different subunits in the eukaryotic proteasome core. Biochemistry. 1994 Oct 11;33(40):12229–12237. [PubMed]
  • Haffter P, Fox TD. Nucleotide sequence of PUP1 encoding a putative proteasome subunit in Saccharomyces cerevisiae. Nucleic Acids Res. 1991 Sep 25;19(18):5075–5075. [PMC free article] [PubMed]
  • Tanaka K, Ii K, Ichihara A, Waxman L, Goldberg AL. A high molecular weight protease in the cytosol of rat liver. I. Purification, enzymological properties, and tissue distribution. J Biol Chem. 1986 Nov 15;261(32):15197–15203. [PubMed]
  • Gaczynska M, Rock KL, Spies T, Goldberg AL. Peptidase activities of proteasomes are differentially regulated by the major histocompatibility complex-encoded genes for LMP2 and LMP7. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9213–9217. [PubMed]
  • Sibille C, Gould KG, Willard-Gallo K, Thomson S, Rivett AJ, Powis S, Butcher GW, De Baetselier P. LMP2+ proteasomes are required for the presentation of specific antigens to cytotoxic T lymphocytes. Curr Biol. 1995 Aug 1;5(8):923–930. [PubMed]
  • Engelhard VH. Structure of peptides associated with class I and class II MHC molecules. Annu Rev Immunol. 1994;12:181–207. [PubMed]
  • Tanaka K, Yoshimura T, Tamura T, Fujiwara T, Kumatori A, Ichihara A. Possible mechanism of nuclear translocation of proteasomes. FEBS Lett. 1990 Oct 1;271(1-2):41–46. [PubMed]
  • Löwe J, Stock D, Jap B, Zwickl P, Baumeister W, Huber R. Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 A resolution. Science. 1995 Apr 28;268(5210):533–539. [PubMed]
  • Ma CP, Slaughter CA, DeMartino GN. Identification, purification, and characterization of a protein activator (PA28) of the 20 S proteasome (macropain). J Biol Chem. 1992 May 25;267(15):10515–10523. [PubMed]
  • Dubiel W, Pratt G, Ferrell K, Rechsteiner M. Purification of an 11 S regulator of the multicatalytic protease. J Biol Chem. 1992 Nov 5;267(31):22369–22377. [PubMed]
  • Gray CW, Slaughter CA, DeMartino GN. PA28 activator protein forms regulatory caps on proteasome stacked rings. J Mol Biol. 1994 Feb 11;236(1):7–15. [PubMed]
  • Ahn JY, Tanahashi N, Akiyama K, Hisamatsu H, Noda C, Tanaka K, Chung CH, Shibmara N, Willy PJ, Mott JD, et al. Primary structures of two homologous subunits of PA28, a gamma-interferon-inducible protein activator of the 20S proteasome. FEBS Lett. 1995 Jun 5;366(1):37–42. [PubMed]
  • Realini C, Dubiel W, Pratt G, Ferrell K, Rechsteiner M. Molecular cloning and expression of a gamma-interferon-inducible activator of the multicatalytic protease. J Biol Chem. 1994 Aug 12;269(32):20727–20732. [PubMed]
  • Honoré B, Leffers H, Madsen P, Celis JE. Interferon-gamma up-regulates a unique set of proteins in human keratinocytes. Molecular cloning and expression of the cDNA encoding the RGD-sequence-containing protein IGUP I-5111. Eur J Biochem. 1993 Dec 1;218(2):421–430. [PubMed]

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