Specialized roles for cysteine cathepsins in health and disease

Abstract

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.

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

“…Among the lysosomal proteases, Cathepsin B has a broad specificity for peptide bonds and has a major role in intracellular protein degradation. 33 These features together with the proposed role of stored lipids in the direct inhibition of this protease 22 and its enhanced expression in hepatic cells from ASMko mice 34 moved us to analyze it in detail. We did not find significant differences in Cathepsin B levels in control and NPA fibroblasts (Figure 7a).…”

Effects of novel human cathepsin S inhibitors on cell migration in human cancer cells

“…The active site cysteine is part of a conserved ''catalytic triad'' formed by cysteine pairing with a histidine, which in turn is paired with an asparagine 18,28 . To determine whether the seven candidate compounds of low IC 50 specifically inhibit Cat S activity 5 , the enzyme activity of recombinant Cat S, Cat L and Cat K were determined after treatment with compounds 6a, 6b, 6e, 6n, 6p, 6r, 6w or E-64 for 10 min (Figure 1).…”

Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia

“…There is growing evidence for specific intra-and extracellular functions for these lysosomal enzymes, which have been shown to participate in numerous cardiovascular pathogeneses and progressions [6][7][8][9][10] . Wang et al 11 reported that CatS activity controlled the production of matrix-derived angiogenic factors (anti-: canstatin, arresten and tumstatin; pro-: g2 fragments), revealing a functional role for CatS in angiogenesis and tumour growth.…”