Dual Role of Cathepsin D: Ligand and Protease

Fusek, Martin; Vĕtvická,

doi:10.5507/bp.2005.003

Cited by 56 publications

(49 citation statements)

References 63 publications

(61 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Because cathepsin D misregulation is implicated in cancer progression (reviewed by Fusek and Vetvicka, 2005;Liaudet-Coopman et al, 2006), altering hSPE-39 levels in vivo may have important consequences. Cathepsin D expression in estrogen receptor-positive breast cancer cells is regulated by estrogen (Cavailles et al, 1993), and a recent study indicates that the hSPE-39 promoter binds estrogen receptor ␣ in a hormone-dependent manner (Laganiere et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

SPE-39 Family Proteins Interact with the HOPS Complex and Function in Lysosomal Delivery

Zhu

Salazar²,

Zlatic³

et al. 2009

MBoC

View full text Add to dashboard Cite

Yeast and animal homotypic fusion and vacuole protein sorting (HOPS) complexes contain conserved subunits, but HOPS-mediated traffic in animals might require additional proteins. Here, we demonstrate that SPE-39 homologues, which are found only in animals, are present in RAB5-, RAB7-, and RAB11-positive endosomes where they play a conserved role in lysosomal delivery and probably function via their interaction with the core HOPS complex. Although Caenorhabditis elegans spe-39 mutants were initially identified as having abnormal vesicular biogenesis during spermatogenesis, we show that these mutants also have disrupted processing of endocytosed proteins in oocytes and coelomocytes. C. elegans SPE-39 interacts in vitro with both VPS33A and VPS33B, whereas RNA interference of VPS33B causes spe-39-like spermatogenesis defects. The human SPE-39 orthologue C14orf133 also interacts with VPS33 homologues and both coimmunoprecipitates and cosediments with other HOPS subunits. SPE-39 knockdown in cultured human cells altered the morphology of syntaxin 7-, syntaxin 8-, and syntaxin 13-positive endosomes. These effects occurred concomitantly with delayed mannose 6-phosphate receptor-mediated cathepsin D delivery and degradation of internalized epidermal growth factor receptors. Our findings establish that SPE-39 proteins are a previously unrecognized regulator of lysosomal delivery and that C. elegans spermatogenesis is an experimental system useful for identifying conserved regulators of metazoan lysosomal biogenesis. INTRODUCTIONLysosome biogenesis is mediated by multiple vesicular budding and fusion events that deliver components between subcellular compartments (Luzio et al., 2003). In Saccharomyces cerevisiae, vesicular fusion at the vacuole (the yeast equivalent of lysosomes) requires the homotypic fusion and vacuole protein sorting (HOPS) complex, which regulates vesicle docking through its interaction with soluble N-ethylmaleimide-sensitive factor-attachment protein receptors (SNAREs) and the Rab protein Ypt7p Sato et al., 2000;Wurmser et al., 2000). The yeast HOPS complex contains class C Vps proteins Vps11p, Vps16p, Vps18p, and Vps33p (Rieder and Emr, 1997) and class B Vps proteins Vps39p and Vps41p (Seals et al., 2000;Wurmser et al., 2000). In addition to vesicular fusion at the vacuole, the class C Vps proteins also function in Golgi-to-endosome transport and other steps in vacuolar delivery pathways (Srivastava et al., 2000;Peterson and Emr, 2001;Subramanian et al., 2004;Peplowska et al., 2007). Involvement of the class C Vps proteins at multiple stages has also been reported in mammalian cells (Kim et al., 2003;Richardson et al., 2004). Vesicular trafficking to the lysosome has been extensively described in yeast (Bowers and Stevens, 2005), but it is also known that this process is more complex in metazoans (Dell'Angelica, 2004). Yeast only has lysosomes of a single type, whereas animals have lysosomes and lysosome-related organelles that are functionally diverse. This diversity is evident when comparing th...

show abstract

Section: Discussionmentioning

confidence: 99%

SPE-39 Family Proteins Interact with the HOPS Complex and Function in Lysosomal Delivery

Zhu

Salazar²,

Zlatic³

et al. 2009

MBoC

View full text Add to dashboard Cite

show abstract

“…The activation peptide (40-60 amino acids) is cleaved off by both auto-proteolysis and proteolysis by other, mainly cysteine lysosomal peptidases that yield active cathepsin D (Fusek and Větvička 2005).…”

Section: Zymogen-activationmentioning

confidence: 99%

“…Cleavage at the so-called β-hairpin loop forms a two-polypeptide chain with a Nterminal, 15-kDa light chain and a C-terminal, 30-kDa heavy chain (Yonezawa et al 1988). In humans, the two chains emerge by cleaving off a small peptide of 7 amino acids between positions 98 through 105 (Fusek and Větvička 2005). Those chains are linked by hydrophobic bonds (Minarowska et al 2008).…”

Section: Zymogen-activationmentioning

confidence: 99%

Aspartic Cathepsin D Endopeptidase Contributes to Extracellular Digestion in Clawed Lobsters Homarus americanus and Homarus gammarus

et al. 2010

View full text Add to dashboard Cite

Acid digestive proteinases were studied in the gastric fluids of two species of clawed lobster (Homarus americanus and Homarus gammarus). An active protein was identified in both species as aspartic proteinase by specific inhibition with pepstatin A. It was confirmed as cathepsin D by mass mapping, N-terminal, and full-length cDNA sequencing. Both lobster species transcribed two cathepsin D mRNAs: cathepsin D1 and cathepsin D2. Cathepsin D1 mRNA was detected only in the midgut gland, suggesting its function as a digestive enzyme. Cathepsin D2 mRNA was found in the midgut gland, gonads, and muscle. The deduced amino acid sequence of cathepsin D1 and cathepsin D2 possesses two catalytic DTG active-site motifs, the hallmark of aspartic proteinases. The putatively active cathepsin D1 has a molecular mass of 36.4 kDa and a calculated pI of 4.14 and possesses three potential glycosylation sites. The sequences showed highest similarities with cathepsin D from insects but also with another crustacean cathepsin D. Cathepsin D1 transcripts were quantified during a starvation period using real-time qPCR. In H. americanus, 15 days of starvation did not cause significant changes, but subsequent feeding caused a 2.5-fold increase. In H. gammarus, starvation caused a 40% reduction in cathepsin D1 mRNA, and no effect was observed with subsequent feeding.

show abstract

“…The role of cathepsin D in biomedical sciences extends its involvement in many pathological processes such as apoptosis, inflammatory states, rheumatic diseases, neoplasms, muscle dystrophy, Alzheimer disease, as well as in their diagnostics [158][159][160][161][162][163][164][165][166][167][168]. The use of inhibitors of cathepsin D biosynthesis, activation and its active form allows regulation of cathepsin D activation.…”

Section: Final Commentsmentioning

confidence: 99%