Exploring Systemic Functions of Lysosomal Proteases: The Perspective of Genetically Modified Mouse Models

Gansz, Martina; Kern, Ursula; Peters, Christoph; Reinheckel, Thomas

doi:10.1007/978-3-7091-0885-7_6

Cited by 3 publications

(5 citation statements)

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“…It will therefore be important in the future to learn even more about the fine-tuned equilibrium of proteases and their endogenous inhibitors (Flütsch and Grütter 2013;Gansz et al 2013;Sloane et al 2013;Turk 2006). Similarly, it will be important to identify in more detail what damage can be caused or which pathways may be affected by the escape of full-length endo-lysosomal cysteine proteases from endolysosomes into the cytosol in cells that remain viable and survive the accidental appearance of hydrolases in the cytoplasm (Lima et al 2013;Reinheckel 2013;Turk and Turk 2009).…”

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

confidence: 97%

“…A more comprehensive approach could be to decipher dysregulation that brings about distress in the form of diseases. This knowledge can then be used for therapeutic approaches in which excessive and pathogenic protease activities are blocked or, in turn, when proteases become excessively activated or aberrantly cleave substrates (Blum 2008;Burden et al 2012;Coussens et al 2002;Deu et al 2012;Gansz et al 2013;Groth-Pedersen and Jaattela 2013;Guay et al 2010;Hook et al 2010;Lah et al 2006;Mason and Joyce 2011;Palermo and Joyce 2008;Puri and Bogyo 2013;Quail and Joyce 2013;Shen 2012;Sloane et al 2013;Turk 2006). It is therefore evident that our future endeavors to understand the roles of proteases in health and disease must be of an inter-disciplinary nature, merging biochemical and cell biological approaches together in order to understand protease function in a global cellular context.…”

Section: The Protease Family Businessmentioning

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%

“…Furthermore, recent understanding of protease functions also includes numerous roles in cellular signaling, thus adding even further to the complexity (Turk and Stoka 2007). To study proteases in specific cellular contexts was the next step that addressed protease activities in different cell types, tissues, or animal models (Akkari et al 2014;Arampatzidou et al 2012;Chan et al 2009;Dauth et al 2011b;Friedrichs et al 2003;Gansz et al 2013;Nakagawa and Rudensky 1999;Reinheckel et al 2001;Sevenich et al 2014;Tamhane et al 2014). Understanding proteolysis in a larger context now includes focusing on the genes encoding proteolytic enzymes including transcriptional and translational regulation (Reiser et al 2010).…”

Section: Introductionmentioning

confidence: 98%

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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: Myths and Common Questionsmentioning

confidence: 97%

Section: The Protease Family Businessmentioning

confidence: 98%

Section: The Protease Family Businessmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

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

et al. 2014

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“…Cathepsins are ubiquitously and redundantly expressed. Hence, cathepsins can be upregulated to take over the function of a related enzyme that has been eliminated by gene knockout or inhibited [227,229,[236][237][238].…”

Section: Virus Internalization and Processing Of Ebov-gpmentioning

confidence: 99%

Interactions of the Ebola virus glycoprotein with host cell factors during viral entry and release

González-Hernández¹

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Ebola virus disease (EVD) is a severe disease that affects humans and non-human primates. The recent EVD epidemic in West Africa shows that EVD poses a severe threat to human health. EVD is caused by Ebola virus (EBOV) and other ebolaviruses, which belong to the family Filoviridae. The EBOV glycoprotein (GP) is the only viral surface protein and mediates host cell entry. Processing of GP by host cell proteases (priming) is required for viral entry into target cells and cathepsin (Cat) B and L have been implicated in GP priming in cell culture. However, these enzymes may be dispensable for viral spread in the infected host and the determinants governing CatB/L dependence of viral entry are incompletely understood. Therefore, the first goal of this thesis was to identify such determinants. Apart from mediating viral entry, EBOV-GP also promotes viral release by antagonizing the interferon-induced antiviral host cell protein tetherin. However, the domains in GP that govern counteraction of tetherin and the contribution of this process to viral spread are incompletely understood. The second aim of the present thesis was thus to identify GP domains and amino acid motifs that control tetherin antagonism.The results of the present thesis show that EBOV-GP-driven entry depends on CatB/L activity irrespective of the shape of the viral particle and the target cell type. Moreover, Calu-3, a human cell line with low endogenous CatL expression, was found to be largely resistant to entry driven by EBOV-GP and other filovirus GPs. Finally, entry was restored by directed expression of CatL or the attachment promoting factor DC-SIGN.Regarding tetherin counteraction by GP, the results obtained show that a GXXXA motif in the transmembrane domain of GP is largely dispensable for GP expression, particle incorporation and host cell entry but is required for tetherin antagonism. Lack of tetherin antagonism was observed in transfected cells and was confirmed in the context of an infectious vesicular stomatitis virus chimera encoding EBOV-GP. In summary, the present thesis identifies Calu-3 cells as one of the few cell lines largely resistant to filovirus GP-driven entry and shows that entry is limited at the stage of attachment and GP priming. Moreover, the results identify a GXXXA motif in GP as essential for tetherin antagonism and provide the first evidence that antagonism can promote viral spread, at least in the context of a surrogate system. The incubation period of EVD ranges from 2 to 21 days in humans [2,18]. Symptoms start abruptly with fever, muscle pain, cough, headache and abdominal pain. During the next phase of the disease symptoms like vomiting, diarrhea, dyspnea, hypovolemic shock, and organ failure occur [19-21]. Studies conducted during the outbreak in West Africa revealed that hemorrhages occur in approximately 5 % of the patients but are the epidemic in West Africa. Moreover, it is being used in the recent outbreak in the Democratic Republic of Congo (DRC) [40,41]. However, it has not been approved by regulatory age...

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Host Cell Proteases: Cathepsins

Brix

2018

Activation of Viruses by Host Proteases

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Exploring Systemic Functions of Lysosomal Proteases: The Perspective of Genetically Modified Mouse Models

Cited by 3 publications

References 86 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

Interactions of the Ebola virus glycoprotein with host cell factors during viral entry and release

Host Cell Proteases: Cathepsins

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