Abstract
Besides their primary involvement in the recycling and degradation of proteins in endo-lysosomal compartments and also in specialized biological functions, cysteine cathepsins are pivotal proteolytic contributors of various deleterious diseases. While the molecular mechanisms of regulation via their natural inhibitors have been exhaustively studied, less is currently known about how their enzymatic activity is modulated during the redox imbalance associated with oxidative stress and their exposure resistance to oxidants. More specifically, there is only patchy information on the regulation of lung cysteine cathepsins, while the respiratory system is directly exposed to countless exogenous oxidants contained in dust, tobacco, combustion fumes, and industrial or domestic particles. Papain-like enzymes (clan CA, family C1, subfamily C1A) encompass a conserved catalytic thiolate-imidazolium pair (Cys25-His159) in their active site. Although the sulfhydryl group (with a low acidic pKa) is a potent nucleophile highly susceptible to chemical modifications, some cysteine cathepsins reveal an unanticipated resistance to oxidative stress. Besides an introductory chapter and peculiar attention to lung cysteine cathepsins, the purpose of this review is to afford a concise update of the current knowledge on molecular mechanisms associated with the regulation of cysteine cathepsins by redox balance and by oxidants (e.g., Michael acceptors, reactive oxygen, and nitrogen species).
Highlights
Proteases are classified into six distinct types according to residues essential for their enzymatic activity and their catalytic mechanism: serine proteases, acid proteases, cysteine proteases, metalloproteases, and threonine proteases [1,2]
We will focus on basic mechanisms of oxidation of thiol functions followed by an update of the current knowledge of the regulation of cysteine cathepsins by oxidants
We showed that CatB participates in the TGF-β1-driven differentiation of lung fibroblasts via the intracellular processing of pro-TGF-β1 to its 25-kDa mature form
Summary
Proteases are classified into six distinct types according to residues essential for their enzymatic activity and their catalytic mechanism: serine proteases, acid (aspartate and glutamate) proteases, cysteine proteases, metalloproteases, and threonine proteases [1,2]. Under specific pathophysiological conditions, truncated cathepsins could be targeted to mitochondria or found in the cytosol before being imported into the nuclear compartment, where they can even function as active proteases [10,11]. This unexpected cellular roadmap was nicely sumIntm. COPD (chronic obstructive pulmonary disease) is a lung pathology that is characterized by progressive and irreversible airflow blockade There is both an obstruction of the airways (chronic bronchitis) and destruction of the alveolar walls (emphysema), aggravated by exacerbation phases (bacterial or viral infections). We will focus on basic mechanisms of oxidation of thiol functions followed by an update of the current knowledge of the regulation of cysteine cathepsins by oxidants
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