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Gene Review

Lnpep  -  leucyl/cystinyl aminopeptidase

Mus musculus

Synonyms: 2010309L07Rik, 4732490P18Rik, CAP, Cystinyl aminopeptidase, IRAP, ...
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Disease relevance of Lnpep

  • We show here that a single subcutaneous immunization in mice with immunostimulating complexes containing either purified intact gp160 envelope glycoprotein of the human immunodeficiency virus (HIV)-1 or influenza haemagglutinin results in reproducible and long-lasting priming of HIV specific or influenza-specific CD8+, MHC class I restricted CTL [1].
  • We show that mucosal immunization of vaccinia-immune BALB/c mice with recombinant vaccinia expressing HIV gp160 induced specific serum antibody and strong HIV-specific cytotoxic T lymphocyte responses [2].
  • In addition to the difference in the molecular weight of two of these antigens, gp160, S25, and gp120r can be distinguished on the basis of differential expression on a panel of cultured renal cancers and normal kidney epithelium and fetal kidney cells [3].
  • Previous studies have shown that treatment of S91-C2 murine melanoma cells with beta-all-trans-retinoic acid (RA) results in growth inhibition, enhanced activity of sialyltransferase, and increased glycosylation of a Mr 160,000 cell surface sialoglycoprotein (gp160) [4].
  • HIV-1 neutralizing antibodies in the genital and respiratory tracts of mice intranasally immunized with oligomeric gp160 [5].

High impact information on Lnpep

  • T lymphocytes from mice and healthy humans immunized against the human immunodeficiency virus (HIV) envelope have recently been shown to recognize two antigenic regions of the gp160 HIV-envelope protein which have been located on the basis of amphipathicity [6].
  • IL-2 and IL-15 were evaluated in vaccinia vectors expressing HIV gp160 for the establishment of an effective vaccine strategy [7].
  • Spleen cells from vaccinia-infected control mice displayed strong CD8+ cytolytic activity against gp160-transfected fibroblasts and fibroblasts pulsed with a peptide (P18) representing a CTL epitope of gp160 [8].
  • Interestingly, the NIH-PPAR gamma cells show normal insulin-dependent translocation of IRAP and form an insulin-responsive vesicular compartment as assessed by cell surface biotinylation and sucrose velocity gradient analysis, respectively [9].
  • In parallel, microinjection of 18c/pep3 but not a control peptide inhibited the insulin-stimulated translocation of endogenous GLUT4 and insulin-responsive amino peptidase (IRAP) to the plasma membrane [10].

Chemical compound and disease context of Lnpep


Biological context of Lnpep


Anatomical context of Lnpep

  • In this study we have characterized this aminopeptidase, referred to as vp165, in 3T3-L1 adipocytes [20].
  • Insulin-regulated aminopeptidase (IRAP) is an abundant cargo protein of Glut4 storage vesicles (GSVs) that traffics to and from the plasma membrane in response to insulin [21].
  • Basal and insulin-stimulated glucose uptake in extensor digitorum longus muscle, and adipocytes isolated from IRAP-/- mice were decreased by 30-60% but were normal for soleus muscle from male IRAP-/- mice [16].
  • Thus, GLUT4 and IRAP content of early endosome-derived sorting vesicles and of IRVs are coordinately regulated, and both proteins are required for maintenance of key constituents of these compartments in cardiac muscle cells in vivo [22].
  • MHC II-mediated T cell proliferation assays performed with cloned human cell lines showed that gp160/LAMP stimulated greater responses than did the wild type gp160 [19].

Associations of Lnpep with chemical compounds

  • Whereas IRAP-/- mice responded to glucose administration like control mice, they exhibited an impaired response to insulin [16].
  • In H-2d mice, the immunodominant determinant of the HIV-1-IIIB gp160 envelope glycoprotein recognized by CD8+ CTL is represented by a 15-residue synthetic peptide (315-329: RIQRGPGRAFVTIGK) [23].
  • In this study, nasal immunization of mice with o-gp160, formulated with liposomes containing monophosphoryl lipid A (MPL), MPL-AF, proteosomes, emulsomes, or proteosomes with emulsomes elicited strong gp160-specific IgG and IgA responses in serum as well as vaginal, lung, and intestinal washes and fecal pellets [5].
  • The precursor gp160 was then isolated by preparative polyacrylamide gel electrophoresis [24].
  • Transmission electron microscopy images of late LPC-1 cells suggested an active protein synthesis which correlated with a more intense deposition of ruthenium red and an increasing amount of gp160 on the cell surface [25].

Regulatory relationships of Lnpep

  • These data suggest that the amino terminus of IRAP interacts with a retention/sorting protein that also regulates the distribution of Glut4 in insulin-responsive cells [26].
  • However, GLUT4 but not vp165 is additionally localised in the regulated secretory pathway in atrial cardiomyocytes [27].

Other interactions of Lnpep

  • Our results show that GLUT4 overexpression or deficiency affects the amount of other GLUT4-vesicle proteins including IRAP and VAMP2 and that GLUT4 sequestration is saturable [28].
  • A fusion protein containing only 28 amino acids from IRAP (GST-IRAP-(55-82)) was as effective in increasing cell surface Glut4 as stimulation with 100 nM insulin (44% versus 43%, respectively) [26].
  • Both preparations also had comparable levels of secretory carrier membrane proteins and of aminopeptidase activity (gp160) [29].
  • Immunoabsorption of intracellular vesicles with anticellugyrin antibodies revealed that IRAP content was reduced by 70% in both cellugyrin-positive and cellugyrin-negative vesicles [22].
  • Nasal immunization of normal mice with HIVgp160-encapsulated hemagglutinating virus of Japan (HVJ)-liposome induced high titers of gp160-specific neutralizing IgG in serum and IgA in nasal wash, saliva, fecal extract, and vaginal wash, along with both Th1- and Th2-type responses [17].

Analytical, diagnostic and therapeutic context of Lnpep

  • By immunofluorescence, p115 partially colocalizes with GLUT4 and IRAP in the perinuclear region of cultured fat cells [21].
  • The subcellular distributions of vp165 and Glut4 were determined by immunoisolation of vesicles with antibodies against both proteins, by immunofluorescence, and by subcellular fractionation and immunoblotting [20].
  • Microinjection into 3T3-L1 adipocytes of a glutathione S-transferase (GST) fusion protein containing the cytosolic portion of IRAP (GST-IRAP-(1-109)), resulted in translocation of Glut4 to the cell surface [26].
  • Immunogold electron microscopy revealed that overexpression of GLUT4 in adipocytes increased the number of GLUT4 molecules per vesicle nearly 2-fold and the number of GLUT4 and IRAP-containing vesicles per cell 3-fold [28].
  • Using sucrose gradient centrifugation and cell surface biotinylation, we found that IRAP content in 50-80S vesicles where GLUT4 vesicles normally sediment was markedly depleted in G4H-/- hearts, and the remaining IRAP was found in the heavy membrane fraction [22].


  1. Induction of CD8+ cytotoxic T cells by immunization with purified HIV-1 envelope protein in ISCOMs. Takahashi, H., Takeshita, T., Morein, B., Putney, S., Germain, R.N., Berzofsky, J.A. Nature (1990) [Pubmed]
  2. Mucosal vaccination overcomes the barrier to recombinant vaccinia immunization caused by preexisting poxvirus immunity. Belyakov, I.M., Moss, B., Strober, W., Berzofsky, J.A. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  3. Cell surface antigens of human renal cancer defined by mouse monoclonal antibodies: identification of tissue-specific kidney glycoproteins. Ueda, R., Ogata, S., Morrissey, D.M., Finstad, C.L., Szkudlarek, J., Whitmore, W.F., Oettgen, H.F., Lloyd, K.O., Old, L.J. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  4. Growth inhibition of murine melanoma cells by antibodies to a cell surface glycoprotein implicated in retinoic acid action. Lotan, R., Lotan, D., Deutsch, V. Cancer Res. (1987) [Pubmed]
  5. HIV-1 neutralizing antibodies in the genital and respiratory tracts of mice intranasally immunized with oligomeric gp160. VanCott, T.C., Kaminski, R.W., Mascola, J.R., Kalyanaraman, V.S., Wassef, N.M., Alving, C.R., Ulrich, J.T., Lowell, G.H., Birx, D.L. J. Immunol. (1998) [Pubmed]
  6. Interleukin-2 production used to detect antigenic peptide recognition by T-helper lymphocytes from asymptomatic HIV-seropositive individuals. Clerici, M., Stocks, N.I., Zajac, R.A., Boswell, R.N., Bernstein, D.C., Mann, D.L., Shearer, G.M., Berzofsky, J.A. Nature (1989) [Pubmed]
  7. Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity. Oh, S., Berzofsky, J.A., Burke, D.S., Waldmann, T.A., Perera, L.P. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  8. Helminth infection results in decreased virus-specific CD8+ cytotoxic T-cell and Th1 cytokine responses as well as delayed virus clearance. Actor, J.K., Shirai, M., Kullberg, M.C., Buller, R.M., Sher, A., Berzofsky, J.A. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  9. Glut4 storage vesicles without Glut4: transcriptional regulation of insulin-dependent vesicular traffic. Gross, D.N., Farmer, S.R., Pilch, P.F. Mol. Cell. Biol. (2004) [Pubmed]
  10. Munc18c function is required for insulin-stimulated plasma membrane fusion of GLUT4 and insulin-responsive amino peptidase storage vesicles. Thurmond, D.C., Kanzaki, M., Khan, A.H., Pessin, J.E. Mol. Cell. Biol. (2000) [Pubmed]
  11. Polyarginine inhibits gp160 processing by furin and suppresses productive human immunodeficiency virus type 1 infection. Kibler, K.V., Miyazato, A., Yedavalli, V.S., Dayton, A.I., Jacobs, B.L., Dapolito, G., Kim, S.J., Jeang, K.T. J. Biol. Chem. (2004) [Pubmed]
  12. Construction and use of a human immunodeficiency virus vector for analysis of virus infectivity. Page, K.A., Landau, N.R., Littman, D.R. J. Virol. (1990) [Pubmed]
  13. Adjuvanticity of stearyl tyrosine on the antibody response to peptide 503-535 from HIV gp160. Bona, C., Nixon, A., Kennedy, R., Zaghouani, H. AIDS Res. Hum. Retroviruses (1992) [Pubmed]
  14. Comparisons of DNA-mediated immunization procedures directed against surface glycoproteins of human immunodeficiency virus type-1 and hepatitis B virus. Fomsgaard, A., Nielsen, H.V., Nielsen, C., Johansson, K., Machuca, R., Bruun, L., Hansen, J., Buus, S. APMIS (1998) [Pubmed]
  15. Immunohistochemical expression of monoclonal antibody 43-9F in testicular germ cell tumours. Heidenreich, A., Sesterhenn, I.A., Mostofi, F.K., Moul, J.W. Int. J. Androl. (1998) [Pubmed]
  16. Mice deficient in the insulin-regulated membrane aminopeptidase show substantial decreases in glucose transporter GLUT4 levels but maintain normal glucose homeostasis. Keller, S.R., Davis, A.C., Clairmont, K.B. J. Biol. Chem. (2002) [Pubmed]
  17. HIV mucosal vaccine: nasal immunization with gp160-encapsulated hemagglutinating virus of Japan-liposome induces antigen-specific CTLs and neutralizing antibody responses. Sakaue, G., Hiroi, T., Nakagawa, Y., Someya, K., Iwatani, K., Sawa, Y., Takahashi, H., Honda, M., Kunisawa, J., Kiyono, H. J. Immunol. (2003) [Pubmed]
  18. M cell DNA vaccination for CTL immunity to HIV. Wang, X., Hone, D.M., Haddad, A., Shata, M.T., Pascual, D.W. J. Immunol. (2003) [Pubmed]
  19. The enhanced immune response to the HIV gp160/LAMP chimeric gene product targeted to the lysosome membrane protein trafficking pathway. Ruff, A.L., Guarnieri, F.G., Staveley-O'Carroll, K., Siliciano, R.F., August, J.T. J. Biol. Chem. (1997) [Pubmed]
  20. Characterization of the insulin-regulated membrane aminopeptidase in 3T3-L1 adipocytes. Ross, S.A., Scott, H.M., Morris, N.J., Leung, W.Y., Mao, F., Lienhard, G.E., Keller, S.R. J. Biol. Chem. (1996) [Pubmed]
  21. p115 Interacts with the GLUT4 vesicle protein, IRAP, and plays a critical role in insulin-stimulated GLUT4 translocation. Hosaka, T., Brooks, C.C., Presman, E., Kim, S.K., Zhang, Z., Breen, M., Gross, D.N., Sztul, E., Pilch, P.F. Mol. Biol. Cell (2005) [Pubmed]
  22. Regulation of insulin-responsive aminopeptidase expression and targeting in the insulin-responsive vesicle compartment of glucose transporter isoform 4-deficient cardiomyocytes. Abel, E.D., Graveleau, C., Betuing, S., Pham, M., Reay, P.A., Kandror, V., Kupriyanova, T., Xu, Z., Kandror, K.V. Mol. Endocrinol. (2004) [Pubmed]
  23. Structural requirements for class I MHC molecule-mediated antigen presentation and cytotoxic T cell recognition of an immunodominant determinant of the human immunodeficiency virus envelope protein. Takahashi, H., Houghten, R., Putney, S.D., Margulies, D.H., Moss, B., Germain, R.N., Berzofsky, J.A. J. Exp. Med. (1989) [Pubmed]
  24. Characterization of a monoclonal antibody specific for the HIV-1 precursor glycoprotein. Krust, B., Laurent, A.G., Le Guern, A., Jeannequin, O., Montagnier, L., Hovanessian, A.G. AIDS (1988) [Pubmed]
  25. Morphology surface of a mouse plasmacytoma (LPC-1) showing cyclic resistance to immune lysis. Rosenstein, Y., Osornio-Vargas, A.R. Lab. Invest. (1986) [Pubmed]
  26. The amino terminus of insulin-responsive aminopeptidase causes Glut4 translocation in 3T3-L1 adipocytes. Waters, S.B., D'Auria, M., Martin, S.S., Nguyen, C., Kozma, L.M., Luskey, K.L. J. Biol. Chem. (1997) [Pubmed]
  27. The glucose transporter GLUT4 and the aminopeptidase vp165 colocalise in tubulo-vesicular elements in adipocytes and cardiomyocytes. Martin, S., Rice, J.E., Gould, G.W., Keller, S.R., Slot, J.W., James, D.E. J. Cell. Sci. (1997) [Pubmed]
  28. GLUT4 overexpression or deficiency in adipocytes of transgenic mice alters the composition of GLUT4 vesicles and the subcellular localization of GLUT4 and insulin-responsive aminopeptidase. Carvalho, E., Schellhorn, S.E., Zabolotny, J.M., Martin, S., Tozzo, E., Peroni, O.D., Houseknecht, K.L., Mundt, A., James, D.E., Kahn, B.B. J. Biol. Chem. (2004) [Pubmed]
  29. Glut4 is targeted to specific vesicles in adipocytes of transgenic mice overexpressing Glut4 selectively in adipose tissue. Tozzo, E., Kahn, B.B., Pilch, P.F., Kandror, K.V. J. Biol. Chem. (1996) [Pubmed]
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