Cysteine Peptidases of Mammals: Their Biological Roles and Potential Effects in the Oral Cavity and Other Tissues in Health and Disease

Abstract

Cysteine peptidases (CPs) are phylogenetically ubiquitous enzymes that can be classified into clans of evolutionarily independent proteins based on the structural organization of the active site. In mammals, two of the major clans represented in the genome are: the CA clan, whose members share a structure and evolutionary history with papain; and the CD clan, which includes the legumains and caspases. This review focuses on the properties of these enzymes, with an emphasis on their potential roles in the oral cavity. The human genome encodes at least (but possibly no more than) 11 distinct enzymes, called cathepsins, that are members of the papain family C1A. Ten of these are present in rodents, which also carry additional genes encoding other cathepsins and cathepsin-like proteins. Human cathepsins are best known from the ubiquitously expressed lysosomal cathepsins B, H, and L, and dipeptidyl peptidase I (DPP I), which until recently were considered to mediate primarily "housekeeping" functions in the cell. However, mutations in DPP I have now been shown to underlie Papillon-Lefèvre syndrome and pre-pubertal periodontitis. Other cathepsins are involved in tissue-specific functions such as bone remodeling, but relatively little is known about the functions of several recently discovered enzymes. Collectively, CPs participate in multiple host systems that are active in health and in disease. They are involved in tissue remodeling and turnover of the extracellular matrix, immune system function, and modulation and alteration of cell function. Intracellularly, CPs function in diverse processes including normal protein turnover, antigen and proprotein processing, and apoptosis. Extracellularly, they can contribute directly to the degradation of foreign proteins and the extracellular matrix. However, CPs can also participate in proteolytic cascades that amplify the degradative capacity, potentially leading to pathological damage, and facilitating the penetration of tissues by cancer cells. We know relatively little regarding the role of human CPs in the oral cavity in health or disease. Most studies to date have focused on the potential use of the lysosomal enzymes as markers for periodontal disease activity. Human saliva contains high levels of cystatins, which are potent CP inhibitors. Although these proteins are presumed to serve a protective function, their in vivo targets are unknown, and it remains to be discovered whether they serve to control any human CP activity.

Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment

“…Although several of these molecules are associated with neuronal vesicle transport and fusion, they are also known to play a major role in transport of myelin vesicles in oligodendrocytes (Madison et al, 1999). In addition, myelin is normally degraded to FFAs through the endosomal-lysosomal pathway and cathepsin S, which also was upregulated (Table 1B, Protein Processing), is particularly important in the processing of antigenic myelin fragments (Nixon et al, 2000;Dickinson, 2002). Notably, lysosomal alterations appear to be important in aging and AD (Bi et al, 2000;Nixon et al, 2000).…”

Cathepsin H regulated by the thyroid hormone receptors associate with tumor invasion in human hepatoma cells

“…A majority of cathepsins are lysosomal proteases, but some are secreted or membrane associated. The intracellular active form (28-kDa) of CTSH is autocatalyzed from the 41-kDa pro-form at acidic pH conditions and localized within the intercellular compartments (Turk et al, 2000;Dickinson, 2002). The secreted CTSH exists predominantly in a pro-form in the medium.…”

“…These results help elucidate the regulation of CTSH expression by thyroid hormones. The common proteolytic degradation by lysosomal cysteine proteinases could be a general process (Dickinson, 2002). Besides their role inside lysosomes, cysteine proteases degrade proteins outside lysosomes.…”

Application of Label-Free Absolute Quantitative Proteomics in Human Gingival Crevicular Fluid by LC/MSE (Gingival Exudatome)

“…Cystatin B, a neutral cysteine proteinase inhibitor, belonging to the cystatin family that minimizes proteolysis-associated tissue damage in inflammation (Chen et al, 1998;Dickinson, 2002). Proteins belong to the cystatin family such cystatin A, but not cystatin B, C or S, have previously been detected in GCF by immunoblotting or ELISA (Blankenvoorde et al, 1997).…”