Legumain/asparaginyl endopeptidase controls extracellular matrix remodeling through the degradation of fibronectin in mouse renal proximal tubular cells.
Legumain/asparaginyl endopeptidase (EC 3.4.22.34) is a novel cysteine protease that is abundantly expressed in the late endosomes and lysosomes of renal proximal tubular cells. Recently, emerging evidence has indicated that legumain might play an important role in control of extracellular matrix turnover in various pathological conditions such as tumor growth/metastasis and progression of atherosclerosis. We initially found that purified legumain can directly degrade fibronectin, one of the main components of the extracellular matrix, in vitro. Therefore, we examined the effect of legumain on fibronectin degradation in cultured mouse renal proximal tubular cells. Fibronectin processing can be inhibited by chloroquine, an inhibitor of lysosomal degradation, and can be enhanced by the overexpression of legumain, indicating that fibronectin degradation occurs in the presence of legumain in lysosomes from renal proximal tubular cells. Furthermore, in legumain-deficient mice, unilateral ureteral obstruction (UUO)-induced renal interstitial protein accumulation of fibronectin and renal interstitial fibrosis were markedly enhanced. These findings indicate that legumain might have an important role in extracellular matrix remodeling via the degradation of fibronectin in renal proximal tubular cells.
Morita
Yoshikata
Y
Department of Medical Biochemistry, Shiga University of Medical Science, Seta, Otsu 520-2192, Japan.
Araki
Hisazumi
H
Sugimoto
Toshiro
T
Takeuchi
Keisuke
K
Yamane
Takuya
T
Maeda
Toshinaga
T
Yamamoto
Yoshio
Y
Nishi
Katsuji
K
Asano
Masahide
M
Shirahama-Noda
Kanae
K
Nishimura
Mikio
M
Uzu
Takashi
T
Hara-Nishimura
Ikuko
I
Koya
Daisuke
D
Kashiwagi
Atsunori
A
Ohkubo
Iwao
I
D000818:Animals; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005109:Extracellular Matrix / Q000201:enzymology* / Q000473:pathology; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism*; D005355:Fibrosis; D007674:Kidney Diseases / Q000201:enzymology* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D000099240:Asparaginyl Endopeptidase
D003546:Cysteine Endopeptidases; D005353:Fibronectins; D000099240:Asparaginyl Endopeptidase