Intra- and extracellular regulation of activity and processing of legumain by cystatin E/M

Smith, Robert L.; Johansen, Harald Thidemann; Nilsen, Hilde; Haugen, Mads H.; Pettersen, Solveig; Mælandsmo, Gunhild Mari; Abrahamson, Magnus; Solberg, Rigmor

doi:10.1016/j.biochi.2012.07.026

Cited by 45 publications

(48 citation statements)

References 170 publications

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“…Decreased ATP levels due to mitochondrial dysfunction have previously been reported in skeletal muscle cells from patients with type 2 diabetes and in rat L6 GLUT4myc myotubes acquiring impaired glucose metabolism [37], [38]. We have recently shown that bafilomycin A1 (a strong inhibitor of the vacuolar type H + -ATPase) also reduced the activity of legumain [23]. Since the lysosomal H + -ATPase needs ATP to accomplish acidic lysosomal pH [39], our results may indicate that simvastatin could reduce the H + -ATPase activity due to possible ATP-depletion resulting in increased lysosomal pH and thus reduced prolegumain processing.…”

Section: Discussionmentioning

confidence: 69%

“…The intermediate legumain forms are further enzymatically processed to the mature active 36 kDa form. Also, prolegumain has been reported to be secreted as well as being associated with integrins [13], and can be internalized and subsequently autoactivated [23]. Although the biological and pathological roles of legumain are starting to be elucidated, much is still unknown.…”

Section: Introductionmentioning

confidence: 99%

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Simvastatin Inhibits Glucose Metabolism and Legumain Activity in Human Myotubes

et al. 2014

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Simvastatin, a HMG-CoA reductase inhibitor, is prescribed worldwide to patients with hypercholesterolemia. Although simvastatin is well tolerated, side effects like myotoxicity are reported. The mechanism for statin-induced myotoxicity is still poorly understood. Reports have suggested impaired mitochondrial dysfunction as a contributor to the observed myotoxicity. In this regard, we wanted to study the effects of simvastatin on glucose metabolism and the activity of legumain, a cysteine protease. Legumain, being the only known asparaginyl endopeptidase, has caspase-like properties and is described to be involved in apoptosis. Recent evidences indicate a regulatory role of both glucose and statins on cysteine proteases in monocytes. Satellite cells were isolated from the Musculus obliquus internus abdominis of healthy human donors, proliferated and differentiated into polynuclear myotubes. Simvastatin with or without mevalonolactone, farnesyl pyrophosphate or geranylgeranyl pyrophosphate were introduced on day 5 of differentiation. After 48 h, cells were either harvested for immunoblotting, ELISA, cell viability assay, confocal imaging or enzyme activity analysis, or placed in a fuel handling system with [14C]glucose or [3H]deoxyglucose for uptake and oxidation studies. A dose-dependent decrease in both glucose uptake and oxidation were observed in mature myotubes after exposure to simvastatin in concentrations not influencing cell viability. In addition, simvastatin caused a decrease in maturation and activity of legumain. Dysregulation of glucose metabolism and decreased legumain activity by simvastatin points out new knowledge about the effects of statins on skeletal muscle, and may contribute to the understanding of the myotoxicity observed by statins.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Simvastatin Inhibits Glucose Metabolism and Legumain Activity in Human Myotubes

et al. 2014

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“…Notably, legumain is present extracellularly in the tumor microenviroment and associated with matrix as well as cell surfaces [9], [11], [48]. The association of secreted legumain with the extracellular matrix has been repeatedly described [10]–[13], [16], [49], an observation which has instigated the design legumain-activated anti-cancer prodrugs [13]. Furthermore, legumain is able to activate the secreted inactive proenzyme of matrix metalloproteinase-2 [9], [50], the role of which in tumor cell-mediated ECM proteolysis and metastasis has been well established [51].…”

Section: Discussionmentioning

confidence: 99%

The Asparaginyl Endopeptidase Legumain Is Essential for Functional Recovery after Spinal Cord Injury in Adult Zebrafish

Shen

Khatri

et al. 2014

PLoS ONE

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Unlike mammals, adult zebrafish are capable of regenerating severed axons and regaining locomotor function after spinal cord injury. A key factor for this regenerative capacity is the innate ability of neurons to re-express growth-associated genes and regrow their axons after injury in a permissive environment. By microarray analysis, we have previously shown that the expression of legumain (also known as asparaginyl endopeptidase) is upregulated after complete transection of the spinal cord. In situ hybridization showed upregulation of legumain expression in neurons of regenerative nuclei during the phase of axon regrowth/sprouting after spinal cord injury. Upregulation of Legumain protein expression was confirmed by immunohistochemistry. Interestingly, upregulation of legumain expression was also observed in macrophages/microglia and neurons in the spinal cord caudal to the lesion site after injury. The role of legumain in locomotor function after spinal cord injury was tested by reducing Legumain expression by application of anti-sense morpholino oligonucleotides. Using two independent anti-sense morpholinos, locomotor recovery and axonal regrowth were impaired when compared with a standard control morpholino. We conclude that upregulation of legumain expression after spinal cord injury in the adult zebrafish is an essential component of the capacity of injured neurons to regrow their axons. Another feature contributing to functional recovery implicates upregulation of legumain expression in the spinal cord caudal to the injury site. In conclusion, we established for the first time a function for an unusual protease, the asparaginyl endopeptidase, in the nervous system. This study is also the first to demonstrate the importance of legumain for repair of an injured adult central nervous system of a spontaneously regenerating vertebrate and is expected to yield insights into its potential in nervous system regeneration in mammals.

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“…These results indicate that transcription of legumian and its activity were positively regulated by p53. Legumain plays an important role in tumor growth/metastasis [5][6][7][8][9][10][11], and cystatin E/M suppresses legumain activity and its processing [22,23]. …”

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation of the legumain gene by p53 in HCT116 cells

Yamane

Murao

Kato-Ose

et al. 2013

Biochemical and Biophysical Research Communications

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Legumain (EC 3.4.22.34) is an asparaginyl endopeptidase. Strong legumain activity was observed in the mouse kidney, and legumain was found to be highly expressed in tumors. We previously reported that bovine kidney annexin A2 was co-purified with legumain and that legumain cleaved the N-terminal region of annexin A2 at an Asn residue in vitro and in vivo. In this study, we found a p53-binding site in intron 1 of the human legumain gene using computational analysis. To determine whether transcription of the legumain gene is regulated by p53, HCT116 cells were transfected with p53 siRNA and the effect of knockdown of p53 expression on legumain expression was examined. The results showed that expression levels of both legumain mRNA and protein were decreased in the siRNA-treated cells. Furthermore, enzyme activity of legumain was also increased by doxorubicin and its activity was reduced by knockdown of p53 in HCT116 cells. These results suggest that legumain expression and its enzyme activity are regulated by p53.

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Intra- and extracellular regulation of activity and processing of legumain by cystatin E/M

Cited by 45 publications

References 170 publications

Simvastatin Inhibits Glucose Metabolism and Legumain Activity in Human Myotubes

Simvastatin Inhibits Glucose Metabolism and Legumain Activity in Human Myotubes

The Asparaginyl Endopeptidase Legumain Is Essential for Functional Recovery after Spinal Cord Injury in Adult Zebrafish

Transcriptional regulation of the legumain gene by p53 in HCT116 cells

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