Regulation of human cathepsin B by alternative mRNA splicing: homeostasis, fatal errors and cell death

Baici, Antonio; Müntener, Kathrin; Willimann, Anna; Zwicky, Roman

doi:10.1515/bc.2006.125

Cited by 36 publications

(20 citation statements)

References 29 publications

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“…A similar discrepancy in expression patterns has been reported for other ubiquitin ligases (52), and tissue-specific distributions have been reported for different isoforms of lysosomal enzymes (63)(64)(65). These differences in expression could reflect tissue-specific auto-ubiquitination of ubiquitinprotein isopeptide ligases (50,51) or the expression of splice variants.…”

Section: Discussionsupporting

confidence: 66%

Diversity in Tissue Expression, Substrate Binding, and SCF Complex Formation for a Lectin Family of Ubiquitin Ligases

Glenn

Nelson

Wen³

et al. 2008

Journal of Biological Chemistry

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Post-translational modification of proteins regulates many cellular processes. Some modifications, including N-linked glycosylation, serve multiple functions. For example, the attachment of N-linked glycans to nascent proteins in the endoplasmic reticulum facilitates proper folding, whereas retention of high mannose glycans on misfolded glycoproteins serves as a signal for retrotranslocation and ubiquitin-mediated proteasomal degradation. Here we examine the substrate specificity of the only family of ubiquitin ligase subunits thought to target glycoproteins through their attached glycans. The five proteins comprising this FBA family (FBXO2, FBXO6, FBXO17, FBXO27, and FBXO44) contain a conserved G domain that mediates substrate binding. Using a variety of complementary approaches, including glycan arrays, we show that each family member has differing specificity for glycosylated substrates. Collectively, the F-box proteins in the FBA family bind high mannose and sulfated glycoproteins, with one FBA protein, FBX044, failing to bind any glycans on the tested arrays. Site-directed mutagenesis of two aromatic amino acids in the G domain demonstrated that the hydrophobic pocket created by these amino acids is necessary for high affinity glycan binding. All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1), yet FBXO2 bound very little Cullin1, suggesting that FBXO2 may exist primarily as a heterodimer with Skp1. Using subunit-specific antibodies, we further demonstrate marked divergence in tissue distribution and developmental expression. These differences in substrate recognition, SCF complex formation, and tissue distribution suggest that FBA proteins play diverse roles in glycoprotein quality control.

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Section: Discussionsupporting

confidence: 66%

Diversity in Tissue Expression, Substrate Binding, and SCF Complex Formation for a Lectin Family of Ubiquitin Ligases

Glenn

Nelson

Wen³

et al. 2008

Journal of Biological Chemistry

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“…B. Protein variants are those that are derived from alternatively spliced messenger RNA (mRNA) variants, thus emerging from transcription of the same gene but alternative splicing of the precursor mRNA (Baici et al 2006). Alternative splicing of precursor mRNA can occur by several mechanisms, for instance, by exon skipping, through the use of mutually exclusive exons, by using alternative 5′ donor and 3′ acceptor sites, or by intron retention.…”

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

confidence: 99%

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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“…The other mechanism is alternative splicing of mRNA transcripts, which affects the protein expression rate or yields proteins with alternative trafficking patterns. This phenomenon has been thoroughly investigated for cathepsin B in association with rheumatoid arthritis (162) , and alternative splicing has been shown to either facilitate extracellular secretion or promote mitochondrial targeting of the enzyme, resulting in cell death (163,164) . Similarly, alternative splicing of cathepsin L has been associated with cancer (165) .…”

Section: Regulatory Strategies In Papain-like Peptidasesmentioning

confidence: 99%

Papain-like peptidases: structure, function, and evolution

Novinec

Lenarčič²

2013

BioMolecular Concepts

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Papain-like cysteine peptidases are a diverse family of peptidases found in most known organisms. In eukaryotes, they are divided into multiple evolutionary groups, which can be clearly distinguished on the basis of the structural characteristics of the proenzymes. Most of them are endopeptidases; some, however, evolved into exopeptidases by obtaining additional structural elements that restrict the binding of substrate into the active site. In humans, papain-like peptidases, also called cysteine cathepsins, act both as non-specific hydrolases and as specific processing enzymes. They are involved in numerous physiological processes, such as antigen presentation, extracellular matrix remodeling, and hormone processing. Their activity is tightly regulated and dysregulation of one or more cysteine cathepsins can result in severe pathological conditions, such as cardiovascular diseases and cancer. Other organisms can utilize papainlike peptidases for different purposes and they are often part of host-pathogen interactions. Numerous parasites, such as Plasmodium and flukes, utilize papain-like peptidases for host invasion, whereas plants, in contrast, use these enzymes for host defense. This review presents a state-of-the-art description of the structure and phylogeny of papain-like peptidases as well as an overview of their physiological and pathological functions in humans and in other organisms.

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Regulation of human cathepsin B by alternative mRNA splicing: homeostasis, fatal errors and cell death

Cited by 36 publications

References 29 publications

Diversity in Tissue Expression, Substrate Binding, and SCF Complex Formation for a Lectin Family of Ubiquitin Ligases

Diversity in Tissue Expression, Substrate Binding, and SCF Complex Formation for a Lectin Family of Ubiquitin Ligases

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

Papain-like peptidases: structure, function, and evolution

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