Cell Type-specific Functions of the Lysosomal Protease Cathepsin L in the Heart

Spira, Daniel; Stypmann, Jörg; Tobin, Desmond J.; Petermann, Ivonne; Mayer, Christian T.; Hagemann, Sascha; Vasiljeva, Olga; Günther, Thomas; Schüle, Roland; Peters, Christoph; Reinheckel, Thomas

doi:10.1074/jbc.m703447200

Cited by 53 publications

(23 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is also worth noting that dilative cardiomyopathy-associated interstitial fibrosis in Ctsl -/-mice is the only defect in the heart that cannot be rescued by transgenic reexpression of mouse cathepsin L in cardiomyocytes of otherwise cathepsin L-deficient mice (75). These results imply that the observed cardiac fibrosis in Ctsl -/-mice is caused by the absence of cathepsin L from cardiac fibroblasts and not from cardiomyocytes.…”

Section: Figurementioning

confidence: 58%

Specialized roles for cysteine cathepsins in health and disease

Reiser

Adair²,

Reinheckel³

2010

J. Clin. Invest.

Self Cite

515

403

View full text Add to dashboard Cite

A primer on cathepsin biology Cathepsin L transcription and translation. Substantial work has beendone to analyze the promoter regions of the human cathepsin L gene (CTSL) promoter as well as to understand the regulation of different splice variants within the 5′ untranslated region of the transcript (21,22). Of note, one of the splice variants contains a functional internal ribosomal entry site that enables ongoing translation of human cathepsin L under stress conditions, and hypoxia can shut down cap-dependent translation initiation (23). More recent work has focused on the regulation of cathepsin L alternative translation. According to the presence of different forms of cathepsin L in distinct subcellular and extracellular compartments, cathepsin L proteins can be initiated from downstream AUG sites (10), omitting the signal peptide that is normally present at the N terminus of lysosomal cathepsin L that routes the protein to the ER during its synthesis (Figure 2) (10, 24-26 Cathepsins were originally identified as proteases that act in the lysosome. Recent work has uncovered nontraditional roles for cathepsins in the extracellular space as well as in the cytosol and nucleus. There is strong evidence that subspecialized and compartmentalized cathepsins participate in many physiologic and pathophysiologic cellular processes, in which they can act as both digestive and regulatory proteases. In this review, we discuss the transcriptional and translational control of cathepsin expression, the regulation of intracellular sorting of cathepsins, and the structural basis of cathepsin activation and inhibition. In particular, we highlight the emerging roles of various cathepsin forms in disease, particularly those of the cardiac and renal systems.

show abstract

Section: Figurementioning

confidence: 58%

Specialized roles for cysteine cathepsins in health and disease

Reiser

Adair²,

Reinheckel³

2010

J. Clin. Invest.

Self Cite

515

403

View full text Add to dashboard Cite

show abstract

“…It is worth noting the significant transcript abundance increases in the GFP– cell populations, in particular with regards to cathepsin L and the MMPs in 2 dpf and 3 dpf embryos, respectively. Because these enzymes are known to play roles in ECM remodeling in many tissues, including the brain and heart (Felbor et al, 2002; Spira et al, 2007; Reiser et al, 2010), it will be of interest to determine whether their inappropriate expression and activity mediates additional aspects of ML-II pathogenesis. Parallel experiments on ML-II embryos generated in transgenic lines that label different cell populations are ongoing and should further address such tissue-specific mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Excessive activity of cathepsin K is associated with cartilage defects in a zebrafish model of mucolipidosis II

Petrey

Flanagan-Steet

Johnson

et al. 2012

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

SUMMARYThe severe pediatric disorder mucolipidosis II (ML-II; also known as I-cell disease) is caused by defects in mannose 6-phosphate (Man-6-P) biosynthesis. Patients with ML-II exhibit multiple developmental defects, including skeletal, craniofacial and joint abnormalities. To date, the molecular mechanisms that underlie these clinical manifestations are poorly understood. Taking advantage of a zebrafish model of ML-II, we previously showed that the cartilage morphogenesis defects in this model are associated with altered chondrocyte differentiation and excessive deposition of type II collagen, indicating that aspects of development that rely on proper extracellular matrix homeostasis are sensitive to decreases in Man-6-P biosynthesis. To further investigate the molecular bases for the cartilage phenotypes, we analyzed the transcript abundance of several genes in chondrocyte-enriched cell populations isolated from wild-type and ML-II zebrafish embryos. Increased levels of cathepsin and matrix metalloproteinase (MMP) transcripts were noted in ML-II cell populations. This increase in transcript abundance corresponded with elevated and sustained activity of several cathepsins (K, L and S) and MMP-13 during early development. Unlike MMP-13, for which higher levels of protein were detected, the sustained activity of cathepsin K at later stages seemed to result from its abnormal processing and activation. Inhibition of cathepsin K activity by pharmacological or genetic means not only reduced the activity of this enzyme but led to a broad reduction in additional protease activity, significant correction of the cartilage morphogenesis phenotype and reduced type II collagen staining in ML-II embryos. Our findings suggest a central role for excessive cathepsin K activity in the developmental aspects of ML-II cartilage pathogenesis and highlight the utility of the zebrafish system to address the biochemical underpinnings of metabolic disease.

show abstract

“…When cardiomyocyte-specific expression of murine cathepsin L was induced in these cathepsin L-deficient mice, changes in cardiac ultrastructure and function were recovered, but the fibrosis still persisted [62]. It is pointed out that when cathepsin L was overexpressed, not only are these pathologies reduced but there also was a significant attenuation in the activities of caspase-3, caspase-8, and caspase-9 [63].…”

Section: Proteases In Dilated Cardiomyopathymentioning

confidence: 95%

Role of various proteases in cardiac remodeling and progression of heart failure

Müller

Dhalla

2011

Heart Fail Rev

View full text Add to dashboard Cite

It is believed that cardiac remodeling due to geometric and structural changes is a major mechanism for the progression of heart failure in different pathologies including hypertension, hypertrophic cardiomyopathy, dilated cardiomyopathy, diabetic cardiomyopathy, and myocardial infarction. Increases in the activities of proteolytic enzymes such as matrix metalloproteinases, calpains, cathepsins, and caspases contribute to the process of cardiac remodeling. In addition to modifying the extracellular matrix, both matrix metalloproteinases and cathepsins have been shown to affect the activities of subcellular organelles in cardiomyocytes. The activation of calpains and caspases has been identified to induce subcellular remodeling in failing hearts. Proteolytic activities associated with different proteins including caspases, calpain, and the ubiquitin-proteasome system have been shown to be involved in cardiomyocyte apoptosis, which is an integral part of cardiac remodeling. This article discusses and compares how the activities of various proteases are involved in different cardiac abnormalities with respect to alterations in apoptotic pathways, cardiac remodeling, and cardiac dysfunction. An imbalance appears to occur between the activities of some proteases and their endogenous inhibitors in various types of hypertrophied and failing hearts, and this is likely to further accentuate subcellular remodeling and cardiac dysfunction. The importance of inhibiting the activities of both extracellular and intracellular proteases specific to distinct etiologies, in attenuating cardiac remodeling and apoptosis as well as biochemical changes of subcellular organelles, in heart failure has been emphasized. It is suggested that combination therapy to inhibit different proteases may prove useful for the treatment of heart failure.

show abstract

Cell Type-specific Functions of the Lysosomal Protease Cathepsin L in the Heart

Cited by 53 publications

References 50 publications

Specialized roles for cysteine cathepsins in health and disease

Specialized roles for cysteine cathepsins in health and disease

Excessive activity of cathepsin K is associated with cartilage defects in a zebrafish model of mucolipidosis II

Role of various proteases in cardiac remodeling and progression of heart failure

Contact Info

Product

Resources

About