Biosynthetic Processing of Cathepsins and Lysosomal Degradation Are Abolished in Asparaginyl Endopeptidase-deficient Mice

Asparaginyl endopeptidase (AEP)/legumain, an asparagine-specific cysteine proteinase in animals, is an ortholog of plant vacuolar processing enzyme (VPE), which processes the exposed asparagine residues of various vacuolar proteins. In search for its physiological role in mammals, here we generated...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-08, Vol.278 (35), p.33194-33199
Main Authors: Shirahama-Noda, Kanae, Yamamoto, Akitsugu, Sugihara, Kazushi, Hashimoto, Noriyoshi, Asano, Masahide, Nishimura, Mikio, Hara-Nishimura, Ikuko
Format: Article
Language:English
Subjects:
Animals
Asparagine - chemistry
Blotting, Northern
Body Weight
Cathepsins - chemistry
Cysteine Endopeptidases - chemistry
DNA, Complementary - metabolism
Endopeptidases - metabolism
Endosomes - metabolism
Gene Library
Immunoblotting
Kidney - cytology
Kidney - metabolism
Lysosomes - enzymology
Lysosomes - metabolism
Mice
Mice, Transgenic
Microscopy, Electron
Microscopy, Fluorescence
Models, Genetic
Mutation
Plant Proteins - chemistry
Reverse Transcriptase Polymerase Chain Reaction
RNA - metabolism
Tissue Distribution
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Summary:Asparaginyl endopeptidase (AEP)/legumain, an asparagine-specific cysteine proteinase in animals, is an ortholog of plant vacuolar processing enzyme (VPE), which processes the exposed asparagine residues of various vacuolar proteins. In search for its physiological role in mammals, here we generated and characterized AEP-deficient mice. Although their body weights were significantly reduced, they were normally born and fertile. In the wild-type kidney where the expression of AEP was exceedingly high among various organs, the localization of AEP was mainly found in the lamp-2-positive late endosomes in the apical region of the proximal tubule cells. In these cells of AEP-deficient mice, the lamp-2-positive membrane structures were found to be greatly enlarged. These aberrant lysosomes, merged with the late endosomes, accumulated electron-dense and membranous materials. Furthermore, the processing of the lysosomal proteases, cathepsins B, H, and L, from the single-chain forms into the two-chain forms was completely defected in the deficient mice. Thus, the AEP deficiency caused the accumulation of macromolecules in the lysosomes, highlighting a pivotal role of AEP in the endosomal/lysosomal degradation system.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M302742200