Cathepsins: Getting in Shape for Lysosomal Proteolysis

Erickson, Ann H.; Isidoro, Ciro; Mach, Lukas; Mort, John S.

doi:10.1007/978-3-7091-0885-7_4

Cited by 10 publications

(21 citation statements)

References 290 publications

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“…Once again, mannose 6-phosphate may serve as a recognition motif for binding of proteases to specific cell surface receptors, but this is not always necessary (Munier-Lehmann et al 1996;Pohlmann et al 1989;von Figura 1991). Other modifications which may lead to receptor-mediated endocytosis include glycosylation or other post-translational modifications beyond mannose 6-phosphorylation but have not been studied exhaustively for cysteine cathepsins (Canuel et al 2009;Coutinho et al 2012Coutinho et al , 2014Erickson et al 2013;Mort and Buttle 1997).…”

Section: Endo-lysosomal Cysteine Peptidases From a Canonical Perspectivementioning

confidence: 97%

“…Whether sorting in the TGN relies entirely, partly, or not at all on mannose 6-phosphorylation of the zymogen forms of endo-lysosomal hydrolases largely depends on the cell type. Sorting independent of the mannose 6-phosphate moiety does occur; however, the underlying principles and molecular mechanisms still require further research in many cases (Brix et al 2008Coutinho et al 2012;de Duve 2005;Erickson et al 2013;Kornfeld and Mellman 1989;Linke et al 2002a;Tedelind et al 2011;von Figura 1991).…”

Section: Endo-lysosomal Cysteine Peptidases From a Canonical Perspectivementioning

confidence: 98%

“…Spatiotemporally controlled protease actions also contribute to cellular fate decisions leading to proliferation, differentiation, or death (Ashkenazi and Salvesen 2014;Flütsch and Grütter 2013;Repnik et al 2012;Turk and Turk 2009). Proteases can also act promiscuously as demonstrated by the efficient, digestive activities of the pancreatic enzymes trypsin and chymotrypsin (Halangk et al 2000) or the endo-lysosomal cysteine cathepsins (Brix 2005;Brix et al 2008Brix et al , 2013Erickson et al 2013;Gansz et al 2013;Joyce and Hanahan 2004;Mohamed and Sloane 2006;Reinheckel et al 2001;Reiser et al 2010;Sloane et al 2013;Turk 2012). However, highly specialized proteases also exist such as the sheddases (Brooks and Lemieux 2013;Grötzinger and Rose-John 2013;Urban and Dickey 2011;Urban and Freeman 2002;Vinothkumar and Freeman 2013) that process their substrates-transmembrane proteins-with a precision that can take quite some time.…”

Section: The Protease Family Businessmentioning

confidence: 98%

“…It starts with their synthesis at the rough endoplasmic reticulum (rER) (Fig. 1) (Brix 2005;Brix et al 2008;Erickson et al 2013;Jordans et al 2009;Linke et al 2002a;Mort and Buttle 1997;Tedelind et al 2011;Varki and Kornfeld 1980;Wiederanders et al 2003). It is well understood how the nascent chains enter the lumen of the rER co-translationally for completion of protein biosynthesis yielding the proteolytically inactive, latent proenzymes.…”

Section: Endo-lysosomal Cysteine Peptidases From a Canonical Perspectivementioning

confidence: 98%

“…Moreover, both cysteine cathepsins and legumain are also detected in the extracellular space, and they are even present in secretory vesicles of specific cell types not only as zymogens but importantly also as the mature and active proteases (Brix et al 2008;Hook et al 2008Hook et al , 2012Tamhane et al 2014;Tooze et al 1991). Hence, it is becoming clear that as new themes emerge, traditional concepts have to be challenged (Brix et al 2008Erickson et al 2013;Hook et al 2012;Tooze et al 1990). The compartments of the secretory and endocytic pathways need to be redefined, in particular, where these two pathways may merge (Fig.…”

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

confidence: 99%

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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 From a Canonical Perspectivementioning

confidence: 97%

Section: Endo-lysosomal Cysteine Peptidases From a Canonical Perspectivementioning

confidence: 98%

Section: The Protease Family Businessmentioning

confidence: 98%

Section: Endo-lysosomal Cysteine Peptidases From a Canonical Perspectivementioning

confidence: 98%

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

confidence: 99%

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

et al. 2014

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The Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders

Vidoni

Follo

Savino

et al. 2016

Medicinal Research Reviews

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123

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In familial neurodegenerative disorders, protein aggregates form continuously because of genetic mutations that drive the synthesis of truncated or unfolded proteins. The oxidative stress imposed by neurotransmitters and environmental neurotoxins constitutes an additional threat to the folding of the proteins and the integrity of organelle membranes in neurons. Failure in degrading such altered materials compromises the function of neurons and eventually leads to neurodegeneration. The lysosomal proteolytic enzyme Cathepsin D is the only aspartic-type protease ubiquitously expressed in all the cells of the human body, and it is expressed at high level in the brain. In general, cathepsin D mediated proteolysis is essential to neuronal cell homeostasis through the degradation of unfolded or oxidized protein aggregates delivered to lysosomes via autophagy or endocytosis. More specifically, many altered neuronal proteins that hallmark neurodegenerative diseases (e.g., the amyloid precursor, α-synuclein, and huntingtin) are physiologic substrates of cathepsin D and would abnormally accumulate if not efficiently degraded by this enzyme. Furthermore, experimental evidence indicates that cathepsin D activity is linked to the metabolism of cholesterol and of glycosaminoglycans, which accounts for its involvement in neuronal plasticity. This review focuses on the unique role of cathepsin D mediated proteolysis in the pathogenesis of human neurodegenerative diseases.

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Host Cell Proteases: Cathepsins

Brix

2018

Activation of Viruses by Host Proteases

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Cathepsins: Getting in Shape for Lysosomal Proteolysis

Cited by 10 publications

References 290 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

The Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders

Host Cell Proteases: Cathepsins

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