The Ins and Outs of Cathepsins: Physiological Function and Role in Disease Management

Abstract

Cathepsins are the most abundant lysosomal proteases that are mainly found in acidic endo/lysosomal compartments where they play a vital role in intracellular protein degradation, energy metabolism, and immune responses among a host of other functions. The discovery that cathepsins are secreted and remain functionally active outside of the lysosome has caused a paradigm shift. Contemporary research has unraveled many versatile functions of cathepsins in extralysosomal locations including cytosol and extracellular space. Nevertheless, extracellular cathepsins are majorly upregulated in pathological states and are implicated in a wide range of diseases including cancer and cardiovascular diseases. Taking advantage of the differential expression of the cathepsins during pathological conditions, much research is focused on using cathepsins as diagnostic markers and therapeutic targets. A tailored therapeutic approach using selective cathepsin inhibitors is constantly emerging to be safe and efficient. Moreover, recent development of proteomic-based approaches for the identification of novel physiological substrates offers a major opportunity to understand the mechanism of cathepsin action. In this review, we summarize the available evidence regarding the role of cathepsins in health and disease, discuss their potential as biomarkers of disease progression, and shed light on the potential of extracellular cathepsin inhibitors as safe therapeutic tools.

Key Matrix Remodeling Enzymes: Functions and Targeting in Cancer

“…Under physiological conditions, cathepsins are mainly localized in lysosomes, a compartment with acidic pH, optimal for their activation, where they play role in immune response, antigen processing, autophagy and intracellular protein degradation. Rupture of the lysosomal membrane, induced by reactive oxygen species (ROS) or other stimuli, allows cathepsins to translocate to other cellular compartments and exert their actions, even though the pH in these compartments is neutral and, as such, not optimal [ 178 ]. In tumors, cathepsins are often found overexpressed and have been recognized as predictive markers for disease progression and therapy response [ 168 , 179 ].…”

ALG-097111, a potent and selective SARS-CoV-2 3-chymotrypsin-like cysteine protease inhibitor exhibits in vivo efficacy in a Syrian Hamster model

“…In addition, cysteine cathepsins are key regulators of both the innate and adaptive immunity to pathogens [ 25 , 26 ]. In particular, Cathepsin L primes T-cells by processing the antigens in the lysosomal compartment of Antigen Presenting Cells (APC's), by presenting the proteolytic degradation peptides on the MHC class II [ 27 ], processing the MHC class II [ 28 ] and different Toll-like receptors (TLR3, -7 and –9) [ 29 , 30 ] and by controlling the secretion of different cytokines [ 25 , 26 ]. Therefore, 3CLpro inhibitors that lack selectivity toward cathepsin L, may potentially have counter-effective side effects by dampening the immune response against SARS-CoV-2 [ 31 ].…”

ALG-097111, a potent and selective SARS-CoV-2 3-chymotrypsin-like cysteine protease inhibitor exhibitsin vivoefficacy in a Syrian Hamster model

“…[24] Although lung tissue cells express both cathepsins and TMPRSS2, many cell-lines commonly used for screening, such as A549, lack TMPRSS2. [27] processing the MHC class II [28] and different Toll-like receptors (TLR3, -7 and -9) [29], [30] and by controlling the secretion of different cytokines [25] [26]. Therefore, 3CLpro inhibitors that lack selectivity toward cathepsin L, may potentially have counter-effective side effects by dampening the immune response against SARS-CoV-2 [31].…”