Browse > Article

HtrA2 Interacts with Aβ Peptide but Does Not Directly Alter Its Production or Degradation  

Liu, Meng-Lu (Department of Microbiology and Research Center for Industrial Development of Biofood Materials, Chonbuk National University Medical School)
Liu, Ming-Jie (Department of Microbiology and Research Center for Industrial Development of Biofood Materials, Chonbuk National University Medical School)
Kim, Jin-Man (Department of Microbiology and Research Center for Industrial Development of Biofood Materials, Chonbuk National University Medical School)
Kim, Hyeon-Jin (Jinis Biopharmaceuticals Company)
Kim, Jeong-Hak (Jinis Biopharmaceuticals Company)
Hong, Seong-Tshool (Department of Microbiology and Research Center for Industrial Development of Biofood Materials, Chonbuk National University Medical School)
Abstract
HtrA2/Omi is a mammalian mitochondrial serine protease homologous to the E. coli HtrA/DegP gene products. Recently, HtrA2/Omi was found to have a dual role in mammalian cells, acting as an apoptosis-inducing protein and being involved in maintenance of mitochondrial homeostasis. By screening a human brain cDNA library with $A{\beta}$ peptide as bait in a yeast two-hybrid system, we identified HtrA2/Omi as a binding partner of $A{\beta}$ peptide. The interaction between $A{\beta}$ peptide and HtrA2/Omi was confirmed by an immunoblot binding assay. The possible involvement of HtrA2/Omi in $A{\beta}$ peptide metabolism was investigated. In vitro peptide cleavage assays showed that HtrA2/Omi did not directly promote the production of $A{\beta}$ peptide at the ${\beta}/{\gamma}$-secretase level, or the degradation of $A{\beta}$ peptide. However, overexpression of HtrA2/Omi in K269 cells decreased the production of $A{\beta}40$ and $A{\beta}42$ by up to 30%. These results rule out the involvement of HtrA2/Omi in the etiology of Alzheimer's disease. However, the fact that overexpression of HtrA2/Omi reduces the generation of $A{\beta}40$ and $A{\beta}42$ suggests that it may play some positive role in mammalian cells.
Keywords
$A{\beta}$ Peptide; Alzheimer's Disease; Apoptosis; HtrA2/Omi; Mitochondria Homeostasis; Secretase;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
Times Cited By Web Of Science : 11  (Related Records In Web of Science)
연도 인용수 순위
1 Faccio, L., Fusco, C., Chen, A., Martinotti, S., Bonventre, J. V., et al. (2000) Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia. J. Biol. Chem. 275, 2581-2588   DOI   ScienceOn
2 Fraering, P. C., Ye, W., Strub, J. M., Dolios, G., LaVoie, M. J., et al. (2004) Purification and characterization of the human gamma-secretase complex. Biochemistry 43, 9774-9789   DOI   ScienceOn
3 Kim, H. J., Kim, H. J., Lim, S. C., Kim, S. H., and Kim, T. Y. (2003) Induction of apoptosis and expression of cell cycle regulatory proteins in response to a phytosphingosine derivative in HaCaT human keratinocyte cells. Mol. Cells 16, 331-337
4 Lammich, S., Kojro, E., Postina, R., Gilbert, S., Pfeiffer, R., et al. (1999) Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl. Acad. Sci. USA 96, 3922-3927
5 Martins, L. M., Iaccarino, I., Tenev, T., Gschmeissner, S., Totty, N. F., et al. (2002) The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaperlike motif. J. Biol. Chem. 277, 439-444   DOI   ScienceOn
6 Park, H. J., Seong, Y. M., Choi, J. Y., Kang, S., and Rhim, H. (2004) Alzheimer's disease-associated amyloid beta interacts with the human serine protease HtrA2/Omi. Neurosci. Lett. 357, 63-67   DOI   ScienceOn
7 Selkoe, D. J. (1999) Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399 (Suppl. 6738), A23-31   DOI   ScienceOn
8 Sinha, S., Anderson, J. P., Barbour, R., Basi, G. S., Caccavello, R., et al. (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402, 537-540   DOI   ScienceOn
9 Yang, Q. H., Church-Hajduk, R., Ren, J., Newton, M. L., and Du, C. (2003) Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis. Genes Dev. 17, 1487-1496   DOI   ScienceOn
10 Suzuki, Y., Imai, Y., Nakayama, H., Takahashi, K., Takio, K., et al. (2001) A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol. Cell 8, 613-621   DOI   ScienceOn
11 Spiess, C., Beil, A., and Ehrmann, M. (1999) A temperaturedependent switch from chaperone to protease in a widely conserved heat shock protein. Cell 97, 339-347   DOI   ScienceOn
12 Gong, Y. S., Chang, L., Viola, K. L., Lacor, P. N., Lambert, M. P., et al. (2003) Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc. Natl. Acad. Sci. USA 100, 10417-11422
13 Hansson, C. A., Frykman, S., Farmery, M. R., Tjernberg, L. O., Nilsberth, C., et al. (2004) Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. J. Biol. Chem. 279, 51654-51660   DOI   ScienceOn
14 Hussain, I., Powell, D., Howlett, D. R., Tew, D. G., Meek, T. D., et al. (1999) Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol. Cell. Neurosci. 14, 419-427   DOI   ScienceOn
15 Vaux, D. L. and Silke, J. (2003) HtrA2/Omi, a sheep in Wolf's clothing. Cell 115, 251-253   DOI   ScienceOn
16 Yan, R., Bienkowski, M. J., Shuck, M. E., Miao, H., Tory, M. C., et al. (1999) Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 402, 533- 537   DOI   ScienceOn
17 Martins, L. M., Turk, B. E., Cowling, V., Borg, A., Jarrell, E. T., et al. (2003) Binding specificity and regulation of the serine protease and PDZ domains of HtrA2/Omi. J. Biol. Chem. 278, 49417-49427   DOI   ScienceOn
18 van Loo, G., van Gurp, M., Depuydt, B., Srinivasula, S. M., Rodriguez, I., et al. (2002) The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity. Cell Death Differ. 9, 20-26   DOI
19 Cilenti, L., Lee, Y., Hess, S., Srinivasula, S., Park, K. M., et al. (2003) Characterization of a novel and specific inhibitor for the pro-apoptotic protease Omi/HtrA2. J. Biol. Chem. 278, 11489-11494   DOI   ScienceOn
20 De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., et al. (1999) A presenilin-1-dependent gamma-secretaselike protease mediates release of Notch intracellular domain. Nature 398, 518-522   DOI   ScienceOn
21 Yu, G., Nishimura, M., Arawaka, S., Levitan, D., Zhang, L., et al. (2000) Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 407, 48-54   DOI   ScienceOn
22 Gray, C. W., Ward, R. V., Karran, E., Turconi, S., Rowles, A., et al. (2000) Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur. J. Biochem. 267, 5699-5710   DOI   ScienceOn
23 Hooper, N. M. and Turner, A. J. (2002) The search for alphasecretase and its potential as a therapeutic approach to Alzheimer's disease. Curr. Med. Chem. 9, 1107-1119   ScienceOn
24 Savopoulos, J. W., Carter, P. S., Turconi, S., Pettman, G. R., Karran, E. H., et al. (2000) Expression, purification, and functional analysis of the human serine protease HtrA2. Protein Exp. Purif. 19, 227-234   DOI   ScienceOn
25 Gupta, S., Singh, R., Datta, P., Zhang, Z., Orr, C., et al. (2004) The C-terminal tail of presenilin regulates Omi/HtrA2 protease activity. J. Biol. Chem. 279, 45844-45854   DOI   ScienceOn
26 Hegde, R., Srinivasula, S. M., Zhang, Z., Wassell, R., Mukattash, R., et al. (2002) Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J. Biol. Chem. 277, 432-438   DOI   ScienceOn
27 Takasugi, N., Tomita, T., Hayashi, I., Tsuruoka, M., Niimura, M., et al. (2003) The role of presenilin cofactors in the gammasecretase complex. Nature 422, 438-441   DOI   ScienceOn
28 Martins, L. M., Morrison, A., Klupsch, K., Fedele, V., Moisoi, N., et al. (2004) Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol. Cell. Biol. 24, 9848-9862   DOI   ScienceOn
29 Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., et al. (1999) Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735-741   DOI   ScienceOn
30 Verhagen, A. M., Silke, J., Ekert, P. G., Pakusch, M., Kaufmann, H., et al. (2002) HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J. Biol. Chem. 277, 445-454   DOI   ScienceOn
31 Yan, S. D., Fu, J., Soto, C., Chen, X., Zhu, H., et al. (1997) An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer's disease. Nature 389, 689-695   DOI   ScienceOn
32 Jones, J. M., Datta, P., Srinivasula, S. M., Ji, W., Gupta, S., et al. (2003) Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. Nature 425, 721–727   DOI   ScienceOn