β-Amyloid precursor protein is a direct cleavage target of HtrA2 serine protease: Implications for the physiological function of HtrA2 in the mitochondria

Hyo Jin Park, Sang Soo Kim, Young Mo Seong, Kyung Hee Kim, Gwan Goo Hui, Jin Yoon Eun, Sik Min Do, Seongman Kang, Hyangshuk Rhim

Research output: Contribution to journalArticle

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Abstract

The processing and metabolism of amyloid precursor protein (APP) is a major interest in Alzheimer disease (AD) research, because not only amyloid β (Aβ) peptide, but also cellular or mitochondrial APP are intimately involved in cellular dysfunction and AD pathogenesis. Here we demonstrate that APP is directly and efficiently cleaved by the HtrA2 serine protease in vitro and in vivo. Using several APP mutants and N-terminal amino acid sequencing, we identified that the HtrA2-mediated APP cleavage product is the C161 fragment encompassing amino acids 535-695 of APP695. The immunofluorescence and subcellular fractionation studies indicate that APP is partly colocalized with HtrA2 in the mitochondria where HtrA2 can cleave APP under normal conditions. The HtrA2-cleaved C161 fragment was detected in the cytosolic fraction; therefore, we postulate that the C161 fragment is released into the cytosol after cleavage of APP by HtrA2. Interestingly, the level of C161 was remarkably decreased in motor neuron degeneration (mnd2) mice in which the serine protease activity of HtrA2 was greatly reduced. These results show that the protease activity of HtrA2 is essential for the production of C161 and that processing of APP into C161 is a natural event occurring under normal physiological conditions. Our study suggests that the direct cleavage of mitochondrial APP by HtrA2 may prevent mitochondrial dysfunction caused by accumulation of APP and that the regulation of HtrA2 protease activity may be a therapeutic target in AD.

Original languageEnglish
Pages (from-to)34277-34287
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number45
DOIs
Publication statusPublished - 2006 Nov 10

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Mitochondria
Amyloid beta-Protein Precursor
Serine Proteases
Amyloid
Alzheimer Disease
Mitochondrial Proteins
Peptide Hydrolases
Nerve Degeneration
Protein Sequence Analysis
Motor Neurons
Amino Acids
Cytosol
Fluorescent Antibody Technique
Fractionation
Processing
Metabolism
Neurons
Peptides

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Park, Hyo Jin ; Kim, Sang Soo ; Seong, Young Mo ; Kim, Kyung Hee ; Hui, Gwan Goo ; Eun, Jin Yoon ; Do, Sik Min ; Kang, Seongman ; Rhim, Hyangshuk. / β-Amyloid precursor protein is a direct cleavage target of HtrA2 serine protease : Implications for the physiological function of HtrA2 in the mitochondria. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 45. pp. 34277-34287.
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abstract = "The processing and metabolism of amyloid precursor protein (APP) is a major interest in Alzheimer disease (AD) research, because not only amyloid β (Aβ) peptide, but also cellular or mitochondrial APP are intimately involved in cellular dysfunction and AD pathogenesis. Here we demonstrate that APP is directly and efficiently cleaved by the HtrA2 serine protease in vitro and in vivo. Using several APP mutants and N-terminal amino acid sequencing, we identified that the HtrA2-mediated APP cleavage product is the C161 fragment encompassing amino acids 535-695 of APP695. The immunofluorescence and subcellular fractionation studies indicate that APP is partly colocalized with HtrA2 in the mitochondria where HtrA2 can cleave APP under normal conditions. The HtrA2-cleaved C161 fragment was detected in the cytosolic fraction; therefore, we postulate that the C161 fragment is released into the cytosol after cleavage of APP by HtrA2. Interestingly, the level of C161 was remarkably decreased in motor neuron degeneration (mnd2) mice in which the serine protease activity of HtrA2 was greatly reduced. These results show that the protease activity of HtrA2 is essential for the production of C161 and that processing of APP into C161 is a natural event occurring under normal physiological conditions. Our study suggests that the direct cleavage of mitochondrial APP by HtrA2 may prevent mitochondrial dysfunction caused by accumulation of APP and that the regulation of HtrA2 protease activity may be a therapeutic target in AD.",
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β-Amyloid precursor protein is a direct cleavage target of HtrA2 serine protease : Implications for the physiological function of HtrA2 in the mitochondria. / Park, Hyo Jin; Kim, Sang Soo; Seong, Young Mo; Kim, Kyung Hee; Hui, Gwan Goo; Eun, Jin Yoon; Do, Sik Min; Kang, Seongman; Rhim, Hyangshuk.

In: Journal of Biological Chemistry, Vol. 281, No. 45, 10.11.2006, p. 34277-34287.

Research output: Contribution to journalArticle

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T1 - β-Amyloid precursor protein is a direct cleavage target of HtrA2 serine protease

T2 - Implications for the physiological function of HtrA2 in the mitochondria

AU - Park, Hyo Jin

AU - Kim, Sang Soo

AU - Seong, Young Mo

AU - Kim, Kyung Hee

AU - Hui, Gwan Goo

AU - Eun, Jin Yoon

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AU - Kang, Seongman

AU - Rhim, Hyangshuk

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AB - The processing and metabolism of amyloid precursor protein (APP) is a major interest in Alzheimer disease (AD) research, because not only amyloid β (Aβ) peptide, but also cellular or mitochondrial APP are intimately involved in cellular dysfunction and AD pathogenesis. Here we demonstrate that APP is directly and efficiently cleaved by the HtrA2 serine protease in vitro and in vivo. Using several APP mutants and N-terminal amino acid sequencing, we identified that the HtrA2-mediated APP cleavage product is the C161 fragment encompassing amino acids 535-695 of APP695. The immunofluorescence and subcellular fractionation studies indicate that APP is partly colocalized with HtrA2 in the mitochondria where HtrA2 can cleave APP under normal conditions. The HtrA2-cleaved C161 fragment was detected in the cytosolic fraction; therefore, we postulate that the C161 fragment is released into the cytosol after cleavage of APP by HtrA2. Interestingly, the level of C161 was remarkably decreased in motor neuron degeneration (mnd2) mice in which the serine protease activity of HtrA2 was greatly reduced. These results show that the protease activity of HtrA2 is essential for the production of C161 and that processing of APP into C161 is a natural event occurring under normal physiological conditions. Our study suggests that the direct cleavage of mitochondrial APP by HtrA2 may prevent mitochondrial dysfunction caused by accumulation of APP and that the regulation of HtrA2 protease activity may be a therapeutic target in AD.

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