Cystatins

Abstract

Chicken egg white cystatin was first described in the late 1960s. Since then, our knowledge about a superfamily of similar proteins present in mammals, birds, fish, insects, plants and some protozoa has expanded, and their properties as potent peptidase inhibitors have been firmly established. Today, 12 functional chicken cystatin relatives are known in humans, but a few evolutionarily related gene products still remain to be characterized. The type 1 cystatins (A and B) are mainly intracellular, the type 2 cystatins (C, D, E/M, F, G, S, SN and SA) are extracellular, and the type 3 cystatins (L- and H-kininogens) are intravascular proteins. All true cystatins inhibit cysteine peptidases of the papain (C1) family, and some also inhibit legumain (C13) family enzymes. These peptidases play key roles in physiological processes, such as intracellular protein degradation (cathepsins B, H and L), are pivotal in the remodelling of bone (cathepsin K), and may be important in the control of antigen presentation (cathepsin S, mammalian legumain). Moreover, the activities of such peptidases are increased in pathophysiological conditions, such as cancer metastasis and inflammation. Additionally, such peptidases are essential for several pathogenic parasites and bacteria. Thus cystatins not only have capacity to regulate normal body processes and perhaps cause disease when down-regulated, but may also participate in the defence against microbial infections. In this chapter, we have aimed to summarize our present knowledge about the human cystatins.

Proteomic analysis reveals successive aberrations in protein expression from healthy mucosa to invasive head and neck cancer

“…Interestingly, silencing of stratifin in oral squamous cell carcinomas occurred at very similar frequency as that of p16 INK4a and was significantly less frequent in HPV positive oral tumors (Gasco et al, 2002), which are also characterized by p16 INK4a positivity (Andl et al, 1998). The cysteine proteinase inhibitors Cystatin A and B are likely relevant for intracellular protein degradation as well as degradation of the extracellular matrix by cathepsins (for review, see Abrahamson et al (2003)). Cystatin B has also been found downregulated in esophageal squamous cell carcinoma, consistent with our results (Shiraishi et al, 1998).…”

Diverse regulatory roles for lysosomal proteases in the immune response

“…Nonetheless, it appears that efficient and sustained inhibition of the enzyme will be required to fully quench neutrophil granule protease activity [63]. Cathepsin C may itself be regulated by cystatin F. Cystatins are a family of proteinaceous cysteine protease inhibitors, some of which bind very tightly to cathepsin active sites [64]. We recently showed that cystatin F, which is principally found in immune cells, could inhibit cathepsin C [65].…”

Frequent epigenetic inactivation of cystatin M in breast carcinoma

“…Cysteine proteases can be involved in enhanced cell survival and proliferation, escape from immune surveillance, cell adhesion and migration, remodelling and invasion of the extracellular matrix (Nomura and Katunuma, 2005). Cystatins are potent inhibitors of endogenous mammalian lysosomal cysteine proteases and protect cells against uncontrolled proteolysis (Abrahamson et al, 2003). Disturbance of the balance between proteases and their cystatins can lead to irreversible damage and tumour development (Calkins and Sloane, 1995;Henskens et al, 1996).…”