Mammalian cathepsins are cysteine-type proteases involved in key steps of biological and pathological events. Cathepsins are considered tractable drug targets as it is feasible to inhibit their enzymatic activity with small molecules and are therefore of interest to the pharmaceutical industry. Cathepsins are mainly located in the acidic compartments of the cells, like lysosomes and endosomes. In addition, cathepsins are secreted and work in the extracellular space, as well as in the cell cytoplasm and in the nucleus. In particular cathepsin L has a broad cellular distribution in all these compartments. By the use of alternative translation start sides downstream from the first AUG, alternative Cat L forms are generated devoid of the leader sequence. The truncated Cat L proteins are directed to the cytoplasm and the nucleus. Based on its cellular location, Cat L performs different cell biological activities.
Data from LDLrec (low density lipoprotein receptor) and Cat L deficient mice highlight the role of cathepsin L in atherosclerosis, as these mice show a reduced atherosclerotic phenotype (Kitamoto et al., Circulation 2007, 115:2065-75). Likewise, Cat L deficient mice have less severe lesions in the elastase induced model of abdominal aortic aneurism (Sun et al., Arterioscler Thromb Vasc Biol. 2011, 31:2500-8). Cat L contributes to vascular lesion formation by promoting inflammatory cell accumulation, angiogenesis, and protease expression. It is involved in matrix degradation, e.g. elastin and collagen, as a secreted protease, in autophagic cell death as cytoplasmic proteases (Mahmood et al., J. Biol. Chem. 2011, 286:28858-66) or by processing transcription factors like Cux-1 as a nuclear protease (Goulet et al., Mol. Cell. 2004, 14:207-19; Goulet et al., Biol. Chem. 2006, 387:1285-93). Human vascular disease samples from atherosclerotic vasculature or AAA (abdominal aortic aneurism) patients show strong upregulation of Cat L in diseases tissue (Liu et al., Atherosclerosis 2006, 184:302-11).
Cytoplasmic variants of Cat L seem to play a key role in proteinuric diseases. The podocyte is a key cell type maintaining the barrier function of the glomeruli in the kidney. Proinflammatory signals like LPS (lipopolysaccharide) induce Cat L expression. Cytoplasmic Cat L cleaves proteins that regulate the placticity of the cytoskeleton: dynamin and synaptopodin. Cat L deficient mice show reduced proteinurea in models of acute proteinurea (Reiser et al., J. Clin. Invest. 2010, 120:3421-31; Yaddanapudi et al., J. Clin. Invest. 2011, 121:3965-80).
Cat L deficient mice show a reduced metabolic phenotype when challenged towards different diabetic condition. Part of the mechanism is the cleavage of the insulin-receptor on skeletal muscle cells (Yang et al., Nat. Cell. Biol. 2007, 9:970-7), but matrix degradation as well as cleavage of the Cux-1 and its role in leptin signaling also contribute to the metabolic functions of Cat L (Stratigopoulos et al., J. Biol. Chem. 2011, 286:2155-70).
Cat L has also been shown to be upregulated in a variety of cancers ranging from breast, lung, gastric, colon to melanomas and gliomas. The cellular functions of Cat L in mediating apoptosis, lysosomal recyling, and cell invasion, make inhibition of Cat L in cancer an attractive target. The decrease of cell-cell adhesion by Cat L can partly be explained by cleavage of E-cadherin (Gocheva et al., Genes Dev. 2006, 20:543-56). The cleavage of extracellular matrix can also release growth factors from the matrix to interact with cell surface receptors.