Cystatin C Properties Crucial for Uptake and Inhibition of Intracellular Target Enzymes

Wallin, Hanna; Abrahamson, Magnus; Ekström, Ulf

doi:10.1074/jbc.m113.453449

Cited by 30 publications

(51 citation statements)

References 34 publications

(17 reference statements)

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“…Likewise, active legumain is thought to be rapidly inactivated if left unstabilized and upon exposure to neutral pH (Dall and Brandstetter 2012;Overbye et al 2011). When secreted from cells, the presence of the endogenous inhibitors cystatins C and E/M, and to a lesser extent cystatin F, is known to strongly restrict the proteolytic activity of extracellular legumain (Alvarez-Fernandez et al 1999;Smith et al 2014;Wallin et al 2013). Type II cystatin presence has accordingly been shown to inhibit cysteine cathepsin-and legumainpromoted invasion of cancer cells (Briggs et al 2010;Vigneswaran et al 2006).…”

Section: Endo-lysosomal Cysteine Peptidases: Myths and Common Questionsmentioning

confidence: 97%

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

et al. 2014

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Proteases play essential roles in protein degradation, protein processing, and extracellular matrix remodeling in all cell types and tissues. They are also involved in protein turnover for maintenance of homeostasis and protein activation or inactivation for cell signaling. Proteases range in function and specificity, with some performing distinct substrate cleavages, while others accomplish proteolysis of a wide range of substrates. As such, different cell types use specialized molecular mechanisms to regulate the localization of proteases and their function within the compartments to which they are destined. Here, we focus on the cysteine family of cathepsin proteases and legumain, which act predominately within the endo-lysosomal pathway. In particular, recent knowledge on cysteine cathepsins and their primary regulator legumain is scrutinized in terms of their trafficking to endo-lysosomal compartments and other less recognized cellular locations. We further explore the mechanisms that regulate these processes and point to pathological cases which arise from detours taken by these proteases. Moreover, the emerging biological roles of specific forms and variants of cysteine cathepsins and legumain are discussed. These may be decisive, pathogenic, or even deadly when localizing to unusual cellular compartments in their enzymatically active form, because they may exert unexpected effects by alternative substrate cleavage. Hence, we propose future perspectives for addressing the actions of cysteine cathepsins and legumain as well as their specific forms and variants. The increasing knowledge in non-canonical aspects of cysteine cathepsin- and legumain-mediated proteolysis may prove valuable for developing new strategies to utilize these versatile proteases in therapeutic approaches.

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Section: Endo-lysosomal Cysteine Peptidases: Myths and Common Questionsmentioning

confidence: 97%

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

et al. 2014

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“…Our model assumed also that transfer across the intracellular-extracellular space was a concentration-driven process akin to diffusion, but the process may be more complex and involve active secretion, which is known to occur for cystatin C in the endoplasmic reticulum-lysosome pathway (45,47). Wallin et al (47) have recently identified a hydrophobic cystatin C region in the cysteine cathepsin binding region of the molecule that seems to be a crucial determinant of cellular uptake.…”

Section: Discussionmentioning

confidence: 99%

“…Wallin et al (47) have recently identified a hydrophobic cystatin C region in the cysteine cathepsin binding region of the molecule that seems to be a crucial determinant of cellular uptake. We iterated the mass transfer coefficient (K int ), and, therefore, the parameter is likely to represent the combined effects of diffusion, active transport, and perhaps, other cellular processes that might affect the rebound in cystatin C.…”

Section: Discussionmentioning

confidence: 99%

Removal and Rebound Kinetics of Cystatin C in High-Flux Hemodialysis and Hemodiafiltration

Vilar

Boltiador

Viljoen

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background and objectives Cystatin C is a 13.3 kD middle molecule of similar size to b 2 -microglobulin and a marker of GFR in CKD. This study aimed to determine cystatin C kinetics in hemodialysis to understand whether blood concentrations may predict residual renal function and middle-molecule clearance.Design, setting, participants, & measurements Cystatin C removal and rebound kinetics were studied in 24 patients on high-flux hemodialysis or hemodiafiltration. To determine whether cystatin C concentrations are predictable, an iterative two-pool mathematical model was applied.Results Cystatin C was cleared effectively, although less than b 2 -microglobulin (reduction ratios6SD are 39%611 and 51%611). Cystatin C rebounded to 95%65% of predialysis concentration by 12 hours postdialysis. The two-pool kinetic model showed excellent goodness of fit. Modeled extracellular cystatin C pool volume is smaller than that predicted, comprising 25.5%69.2 of total body water. Iterated parameters, including nonrenal clearance, showed wide interindividual variation. Modeled nonrenal clearance was substantially higher than renal clearance in this population at 25.166.6 ml/min per 1.73 m 2 body surface area.Conclusions Plasma cystatin C levels may be used to measure middle-molecule clearance. Levels rebound substantially postdialysis and plateau in the interdialytic period. At low GFR, nonrenal clearance predominates over renal clearance, and its interindividual variation will limit use of cystatin C to predict residual renal function in advanced kidney disease.

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“…Internalized CysC has been shown to co-localize with the lysosomal proteins Cat D and legumain in cultured prostate cancer cells. The activity of both cysteine-protease cathepsins and legumain, enzymes potentially associated with cancer cell invasion and metastasis, was down-regulated in cell homogenates following CysC uptake, suggesting that intracellular cysteine proteases involved in cancer-promoting processes might be controlled by CysC uptake (Wallin et al, 2013). Thus, CysC is found in many of the compartments inside and outside of the cell that contain cathepsins, consistent with the idea that CysC plays a role in the regulation of cathepsin activity both within the endosomal-lysosomal pathway and more broadly when cathepsins are found outside of these compartments.…”

Section: Cathepsins and Cysc Can Interact In Multiple Cellular Commentioning

confidence: 99%

“…Endogenously produced CysC has been found in endosomal-lysosomal cellular compartments, where it was shown to inhibit cathepsin activities within the lysosomal system (Pierre and Mellman, 1998). Exogenous CysC added to cell-culture media is internalized (Ekstrom et al, 2008; Kolodziejczyk et al, 2010; Merz et al, 1997), and internalized CysC co-localized with Cat D in lysosomes (Wallin et al, 2013). Thus, while cells producing CysC can secrete the protein, explaining that soluble CysC is detected in bodily fluids such as CSF and blood plasma (Bobek and Levine, 1992; Turk et al, 2008), subsequent internalization and distribution throughout the endosomal-lysosomal system is consistent with its role in cathepsin inhibition.…”

Section: Introductionmentioning

confidence: 99%

Cystatin C in aging and in Alzheimer’s disease

Mathews

Levy

2016

Ageing Research Reviews

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Under normal conditions, the function of catalytically active proteases is regulated, in part, by their endogenous inhibitors, and any change in the synthesis and/or function of a protease or its endogenous inhibitors may result in inappropriate protease activity. Altered proteolysis as a result of an imbalance between active proteases and their endogenous inhibitors can occur during normal aging, and such changes have also been associated with multiple neuronal diseases, including Amyotrophic Lateral Sclerosis (ALS), rare heritable neurodegenerative disorders, ischemia, some forms of epilepsy, and Alzheimer’s disease (AD). One of the most extensively studied endogenous inhibitor is the cysteine-protease inhibitor cystatin C (CysC). Changes in the expression and secretion of CysC in the brain have been described in various neurological disorders and in animal models of neurodegeneration, underscoring a role for CysC in these conditions. In the brain, multiple in vitro and in vivo findings have demonstrated that CysC plays protective roles via pathways that depend upon the inhibition of endosomal-lysosomal pathway cysteine proteases, such as cathepsin B (Cat B), via the induction of cellular autophagy, via the induction of cell proliferation, or via the inhibition of amyloid-β (Aβ) aggregation. We review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced by CysC under various conditions. Beyond highlighting the essential role that balanced proteolytic activity plays in supporting normal brain aging, these findings suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration.

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Cystatin C Properties Crucial for Uptake and Inhibition of Intracellular Target Enzymes

Cited by 30 publications

References 34 publications

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

Removal and Rebound Kinetics of Cystatin C in High-Flux Hemodialysis and Hemodiafiltration

Cystatin C in aging and in Alzheimer’s disease

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