Protective Protein as an Endogenous Endothelin Degradation Enzyme in Human Tissues

Itoh, Kohji; Kase, Ryoichi; Shimmoto, Michie; Satake, Akira; Sakuraba, Hitoshi; Suzuki, Yoshiyuki

doi:10.1074/jbc.270.2.515

Cited by 60 publications

(31 citation statements)

References 35 publications

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“…In particular, the components of the multienzyme complex, Neu1, CathA, and ␤-galactosidase (or its alternatively spliced elastin-binding form), participate in processing of endothelin-1 (21,33), assembly of the elastic fibers (21,34,35), pro-inflammatory response in macrophages (36), migration, invasion, and adhesion of cancer cells (37), proliferation of aortic smooth muscle cells (38), and exocytosis (39). In humans, genetic defects in CathA cause disruption of the complex and trigger galactosialidosis (MIM 256540), a severe multisystemic disease characterized by combined deficiency of Neu1, ␤-galactosidase, and CathA (for review, see Ref.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Phagocytosis in Macrophages by Neuraminidase 1

Seyrantepe

Iannello

Liang

et al. 2010

Journal of Biological Chemistry

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The differentiation of monocytes into macrophages and dendritic cells is accompanied by induction of cell-surface neuraminidase 1 (Neu1) and cathepsin A (CathA), the latter forming a complex with and activating Neu1. To clarify the biological importance of this phenomenon we have developed the gene-targeted mouse models of a CathA deficiency (CathA S190A ) and a double CathA/Neu1 deficiency (CathA S190A-Neo ). Macrophages of CathA S190A-Neo mice and their immature dendritic cells showed a significantly reduced capacity to engulf Grampositive and Gram-negative bacteria and positively and negatively charged polymer beads as well as IgG-opsonized beads and erythrocytes. Properties of the cells derived from CathA S190A mice were indistinguishable from those of wild-type controls, suggesting that the absence of Neu1, which results in the increased sialylation of the cell surface proteins, probably affects multiple receptors for phagocytosis. Previous data showed that mammalian neuraminidase 1 (Neu1), 5 in addition to its role in the intralysosomal catabolism, may be also involved in cellular signaling during the immune response. In particular, during the activation of mouse T cells, Neu1 is expressed on the plasma membrane and is required for the early production of interleukin-4 and for the interaction of T cells with the antigen-presenting cells (8 -12). In addition, Neu1 of T cells converts the group-specific component (Gc protein) into a factor necessary for the inflammation-primed activation of macrophages (13,14). T cells derived from SM/J or B10.SM strains of mice with the reduced Neu1 activity, due to a missense mutation in the Neu1 gene (15), fail to convert Gc and synthesize interleukin-4, whereas B cells of these mice cannot produce IgG 1 and IgE after immunization with pertussis toxin (8,14,16). Strikingly, surface desialylation of macrophages by viral sialidase from Arthrobacter ureafaciens significantly increases their capacity for phagocytosis of influenza virus-infected HeLa cells (17), providing the direct link between the surface sialylation of antigen-presenting cells and their biological activity.Previously we showed that Neu1 increased 14-fold during the differentiation of human monocytes into macrophages (18). * This work was supported in part by Canadian Institutes of Health ResearchOperating Grants MOP 15079 and GOP 38107 and by an equipment grant from Canadian Foundation for Innovation (to A. V. P.

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Section: Discussionmentioning

confidence: 99%

Regulation of Phagocytosis in Macrophages by Neuraminidase 1

Seyrantepe

Iannello

Liang

et al. 2010

Journal of Biological Chemistry

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“…In addition to its role in the lysosome, CAPP has also been shown to inactivate endothelin, a potent SMC vasoconstrictor and mitogen (41,42). Interestingly, a previous report demonstrated that atRA antagonized endothelin-induced SMC mitogenesis through the attenuation of ERK activity (9).…”

Section: Fig 5 Tissue-restricted Expression Of Risc Mrna Total Rnamentioning

confidence: 99%

Cloning of a Novel Retinoid-inducible Serine Carboxypeptidase from Vascular Smooth Muscle Cells

Chen

Streb²,

Maltby

et al. 2001

Journal of Biological Chemistry

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Retinoids block smooth muscle cell (SMC) proliferation and attenuate neointimal formation after vascular injury, presumably through retinoid receptor-mediated changes in gene expression. To identify target genes in SMC whose encoded proteins could contribute to such favorable biological effects, we performed a subtractive screen for retinoid-inducible genes in cultured SMC. Here, we report on the cloning and initial characterization of a novel retinoid-inducible serine carboxypeptidase (RISC). Expression of RISC is low in cultured SMC but progressively increases over a 5-day time-course treatment with all-trans-retinoic acid. A near full-length rat RISC cDNA was cloned and found to have a 452-amino acid open reading frame containing an aminoterminal signal sequence, followed by several conserved domains comprising the catalytic triad common to members of the serine carboxypeptidase family. In vitro transcription and translation experiments showed that the rat RISC cDNA generates a ϳ51-kDa protein. Confocal immunofluorescence microscopy of COS-7 cells transiently transfected with a RISC-His tag plasmid revealed cytosolic localization of the fusion protein.Western blotting studies using conditioned medium from transfected COS-7 cells suggest that RISC is a secreted protein. Tissue Northern blotting studies demonstrated robust expression of RISC in rat aorta, bladder, and kidney with much lower levels in all other tissues analyzed; high level RISC expression was also observed in human kidney. In situ hybridization verified the localization of RISC to medial SMC of the adult rat aorta. Interestingly, expression in kidney was restricted to proximal convoluted tubules; little or no expression was observed in glomerular cells, distal convoluted and collecting tubules, or medullary cells. Radiation hybrid mapping studies placed the rat RISC locus on chromosome 10q. These studies reveal a novel retinoid-inducible protease whose activity may be involved in vascular wall and kidney homeostasis.

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“…7,13 Studies of cultured fibroblasts from galactosialidosis patients demonstrated that these cells lack endothelin-degrading capacity, whereas brain autopsies showed high ET-1-specific immunoreactivity. 14,15 Because in tissues and in the circulation, ET-1 is also cleaved by an abundant neutral endopeptidase, NEP, 16 in vivo experiments are required to understand whether CathA is a nonredundant ET-1-degrading enzyme. The previously described CathA-knockout mice are not suitable for physiological and behavioral studies because they develop progressive and diffuse edema, tremor, and ataxia due to secondary Neu1 deficiency.…”

mentioning

confidence: 99%

Enzymatic Activity of Lysosomal Carboxypeptidase (Cathepsin) A Is Required for Proper Elastic Fiber Formation and Inactivation of Endothelin-1

et al. 2008

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Background— Lysosomal carboxypeptidase, cathepsin A (protective protein, CathA), is a component of the lysosomal multienzyme complex along with β-galactosidase (GAL) and sialidase Neu1, where it activates Neu1 and protects GAL and Neu1 against the rapid proteolytic degradation. On the cell surface, CathA, Neu1, and the enzymatically inactive splice variant of GAL form the elastin-binding protein complex. In humans, genetic defects of CathA cause galactosialidosis, a metabolic disease characterized by combined deficiency of CathA, GAL, and Neu1 and a lysosomal storage of sialylated glycoconjugates. However, several phenotypic features of galactosialidosis patients, including hypertension and cardiomyopathies, cannot be explained by the lysosomal storage. These observations suggest that CathA may be involved in hemodynamic functions that go beyond its protective activity in the lysosome. Methods and Results— We generated a gene-targeted mouse in which the active CathA was replaced with a mutant enzyme carrying a Ser190Ala substitution in the active site. These animals expressed physiological amounts of catalytically inactive CathA protein, capable of forming lysosomal multienzyme complex, and did not develop secondary deficiency of Neu1 and GAL. Conversely, the mice showed a reduced degradation rate of the vasoconstrictor peptide, endothelin-1, and significantly increased arterial blood pressure. CathA-deficient mice also displayed scarcity of elastic fibers in lungs, aortic adventitia, and skin. Conclusions— Our results provide the first evidence that CathA acts in vivo as an endothelin-1–inactivating enzyme and strongly confirm a crucial role of this enzyme in effective elastic fiber formation.

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Protective Protein as an Endogenous Endothelin Degradation Enzyme in Human Tissues

Cited by 60 publications

References 35 publications

Regulation of Phagocytosis in Macrophages by Neuraminidase 1

Regulation of Phagocytosis in Macrophages by Neuraminidase 1

Cloning of a Novel Retinoid-inducible Serine Carboxypeptidase from Vascular Smooth Muscle Cells

Enzymatic Activity of Lysosomal Carboxypeptidase (Cathepsin) A Is Required for Proper Elastic Fiber Formation and Inactivation of Endothelin-1

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