Mammalian legumain – A lysosomal cysteine protease with extracellular functions?

Lunde, Ngoc Nguyen; Bosnjak, Tatjana; Solberg, Rigmor; Johansen, Harald Thidemann

doi:10.1016/j.biochi.2019.06.002

Cited by 24 publications

(20 citation statements)

References 300 publications

(333 reference statements)

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“…In addition to its intracellular activity, legumain can be secreted into the tumor microenvironment (TME) in which it contributes to degrading and remodeling the ECM [ 16 , 167 ], either by producing the mature forms of MMP2 and MMP9 [ 16 , 168 ] or by processing cathepsins [ 169 ]. In gastric carcinoma, legumain knockdown resulted in changes in downstream EMT signaling pathways (e.g., Twist), with increased E‐cadherin and decreased mesenchymal markers [ 170 ].…”

Section: Lysosomal Peptidases In Cancer Progressionmentioning

confidence: 99%

Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

et al. 2022

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Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and pathologies, either within lysosomes, upon secretion into the cell cytoplasm or extracellular space, or bound to the plasma membrane. In cancer, lysosomal peptidases are generally associated with disease progression, as they participate in crucial processes leading to changes in cell morphology, signaling, migration, and invasion, and finally metastasis. However, they can also enhance the mechanisms resulting in cancer regression, such as apoptosis of tumor cells or antitumor immune responses. Lysosomal peptidases have also been identified as hallmarks of aging and neurodegeneration, playing roles in oxidative stress, mitochondrial dysfunction, abnormal intercellular communication, dysregulated trafficking, and the deposition of protein aggregates in neuronal cells. Furthermore, deficiencies in lysosomal peptidases may result in other pathological states, such as lysosomal storage disease. The aim of this review was to highlight the role of lysosomal peptidases in particular pathological processes of cancer and neurodegeneration and to address the potential of lysosomal peptidases in diagnosing and treating patients.

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Section: Lysosomal Peptidases In Cancer Progressionmentioning

confidence: 99%

Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

et al. 2022

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“…The enzyme was later renamed δ-secretase (Zhang et al, 2015) to highlight its role in APP cleavage at Asn 586 that generates the δ-CTF first identified in the nineties (Simons et al, 1996; Scharfenberg et al, 2019). As lysosomal dysfunction is a transversal pathogenic mechanism, legumain has been involved in numerous pathological settings, including atherosclerosis, osteoporosis, cancer, ischemic stroke, and neurodegenerative diseases (Lunde et al, 2019). Legumain has been described in relation with AD as a modulator of Tau phosphorylation (Basurto-Islas et al, 2013), and as a Tau- or APP-cleaving enzyme (Zhang et al, 2014, 2015).…”

Section: Some Emerging App Processing Proteinasesmentioning

confidence: 99%

Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP

García-González

Piłat

Baranger

et al. 2019

Front. Aging Neurosci.

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Processing of amyloid beta precursor protein (APP) into amyloid-beta peptide (Aβ) by β-secretase and γ-secretase complex is at the heart of the pathogenesis of Alzheimer’s disease (AD). Targeting this proteolytic pathway effectively reduces/prevents pathology and cognitive decline in preclinical experimental models of the disease, but therapeutic strategies based on secretase activity modifying drugs have so far failed in clinical trials. Although this may raise some doubts on the relevance of β- and γ-secretases as targets, new APP-cleaving enzymes, including meprin-β, legumain (δ-secretase), rhomboid-like protein-4 (RHBDL4), caspases and membrane-type matrix metalloproteinases (MT-MMPs/η-secretases) have confirmed that APP processing remains a solid mechanism in AD pathophysiology. This review will discuss recent findings on the roles of all these proteinases in the nervous system, and in particular on the roles of MT-MMPs, which are at the crossroads of pathological events involving not only amyloidogenesis, but also inflammation and synaptic dysfunctions. Assessing the potential of these emerging proteinases in the Alzheimer’s field opens up new research prospects to improve our knowledge of fundamental mechanisms of the disease and help us establish new therapeutic strategies.

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“…AEP activation is autocatalytic and requires the sequential removal of C-terminal and N-terminal propeptides in an optimal acidic environment [ 7 , 8 ]. Although AEP is mainly localized in the acidic endolysosomal system, activated AEP has also been demonstrated to remain active and functional in the cytoplasm, membrane, and extracellular areas [ 9 , 10 ]. The overexpressed AEP is implicated in numerous human diseases, including immune disorders, cancer, and neurological diseases [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1

Lei

Qiu

et al. 2022

Cell Death Dis

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Podocyte injury and loss are critical events in diabetic nephropathy (DN); however, the underlying molecular mechanisms remain unclear. Here, we demonstrate that asparaginyl endopeptidase (AEP) protects against podocyte injury through modulating the dynamics of the cytoskeleton. AEP was highly upregulated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes; however, AEP gene knockout and its compound inhibitor treatment accelerated DN in streptozotocin-induced diabetic mice, whereas specific induction of AEP in glomerular cells attenuated podocyte injury and renal function deterioration. In vitro, elevated AEP was involved in actin cytoskeleton maintenance and anti-apoptosis effects. Mechanistically, we found that AEP directly cleaved the actin-binding protein cofilin-1 after the asparagine 138 (N138) site. The protein levels of endogenous cofilin-1 1-138 fragments were upregulated in diabetic podocytes, consistent with the changes in AEP levels. Importantly, we found that cofilin-1 1-138 fragments were remarkably unphosphorylated than full-length cofilin-1, indicating the enhanced cytoskeleton maintenance activity of cofilin-1 1-138. Then we validated cofilin-1 1-138 could rescue podocytes from cytoskeleton disarrangement and injury in diabetic conditions. Taken together, our data suggest a protective role of elevated AEP in podocyte injury during DN progression through cleaving cofilin-1 to maintain podocyte cytoskeleton dynamics and defend damage.

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Mammalian legumain – A lysosomal cysteine protease with extracellular functions?

Cited by 24 publications

References 300 publications

Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP

Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1

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