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susceptibility or less severe phenotypes in models of arthritis, atherosclerosis, and
various cancers (de Nooijer et al.
2009
; Lutgens et al.
2006
;Nakagawaetal.
1999
;
Palermo and Joyce
2008
; Samokhin et al.
2008
; Schedel et al.
2004
). This indicates
that cysteine proteases may play a critical role in ECM degradation. This chapter will
focus on the involvement of cathepsins in ECM degradation and its pathophysiologi-
cal implications.
2.2 Cysteine Cathepsins (Classification, Structure, Specificity)
The term “cathepsin” was derived from the Greek word for “digesting” and dates
back 80 years (Willstaetter and Bamann
1929
). Originally, it described acidic
proteases isolated from the stomach mucosa. It should be noted that the umbrella
term “cathepsin” comprises proteases from three different mechanistic classes:
cysteine, serine, and aspartic proteases. In this chapter, we will only discuss cysteine
cathepsins, which are also known as papain-like thiol proteases. Papain-like thiol
proteases are the largest subfamily (C1) among the cysteine protease clan CA.
Eleven human thiol-dependent cathepsins are expressed in the human genome
(cathepsins B, L, K, S, V, F, W, H, X, C, and O). The mouse genome contains
ten of the human orthologues and eight additional cathepsins in the placenta (Mason
2008
). Interestingly, mice do not express cathepsin V.
Cathepsins are expressed either ubiquitously or with tissue and cell-type speci-
ficity (Lecaille et al.
2002b
). Cathepsins B, L, and H are found in most if not in all
cell types and tissues and have been attributed to nonspecific bulk protein degrada-
tion in lysosomes. Cathepsins S, K, V, F, C, and W, in contrast, are more selectively
expressed and exhibit cell-type specific functions. Cathepsins S, F, and V are highly
expressed in macrophages, dendritic cells, and/or thymic cortical epithelial cells
and are involved in antigen processing and presentation (Riese and Chapman
2000
;
Shi et al.
2000
; Tolosa et al.
2003
). Cathepsins C and W are also expressed in
immune-related cells. The function of cathepsin C (DPPI) is likely the processing of
diverse precursor proteins including those of serine proteases such as granzyme
zymogens (Pham and Ley
1999
). Cathepsin W is specifically expressed in CD8
and natural killer cells (Linnevers et al.
1997
; Wex et al.
2001
) but its biological
function still remains elusive. Cathepsin O has been described to be highly
expressed in colon cancer cells (Velasco et al.
1994
).
All papain-like cysteine proteases consist of a signal peptide, a propeptide, and a
catalytic domain with the latter representing the mature proteolytically active
enzyme (Fig.
2.1A
). Signal peptides, which are responsible for the translocation
into the endoplasmic reticulum during mRNA translation, are on average between
10 and 20 amino acids in length. Propeptides are of variable length between 36
amino acids in human cathepsin X and 251 amino acids in cathepsin F and have at
least three known functions (Wiederanders et al.
2003
). First, the propeptide acts
as a scaffold for protein folding of the catalytic domain; second, the prodomain acts
as a chaperone for the transport of the proenzyme to the endosomal/lysosomal
