Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

Abstract

Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and pathologies, either within lysosomes, upon secretion into the cell cytoplasm or extracellular space, or bound to the plasma membrane. In cancer, lysosomal peptidases are generally associated with disease progression, as they participate in crucial processes leading to changes in cell morphology, signaling, migration, and invasion, and finally metastasis. However, they can also enhance the mechanisms resulting in cancer regression, such as apoptosis of tumor cells or antitumor immune responses. Lysosomal peptidases have also been identified as hallmarks of aging and neurodegeneration, playing roles in oxidative stress, mitochondrial dysfunction, abnormal intercellular communication, dysregulated trafficking, and the deposition of protein aggregates in neuronal cells. Furthermore, deficiencies in lysosomal peptidases may result in other pathological states, such as lysosomal storage disease. The aim of this review was to highlight the role of lysosomal peptidases in particular pathological processes of cancer and neurodegeneration and to address the potential of lysosomal peptidases in diagnosing and treating patients.

Innovation and renovation: FEBS Open Bio in 2023

“…This issue contained five Review articles focussed on the important role of lysosomes, once thought to be little more than waste disposal units, in health and disease: in their article, Jonathan Martinez‐Fabregas, Irene Díaz‐Moreno and colleagues indicated that the lysosome is part of a complex communication network between organelles, and lysosome dysfunction is linked to a variety of pathologies [ 1 ]. These disease states include cancer and neurodegeneration, as reviewed by Janko Kos and co‐authors in the same issue [ 2 ]. Lysosomes are also implicated in ageing‐related diseases through cross‐talk between the autophagy‐lysosome pathway and mTORC1 activity; Timothy J. Sargeant and colleagues explored this interaction and whether targeting this pathway might slow the ageing process [ 3 ].…”

Dipeptide-Derived Alkynes as Potent and Selective Irreversible Inhibitors of Cysteine Cathepsins

“… 55 In addition to their predominantly extracellular effects associated with cancer, intracellular proteolytic processes mediated by cysteine cathepsins have also been linked to tumor progression. 56 , 57 With regard to the particular function of cathepsin B in neoplastic diseases, the secretion of this cathepsin seems to be regulated by tumor-associated processes. Accordingly, the lower pH in the tumor microenvironment induces the relocation of cathepsin B-containing vesicles to the cell surface and the release of their content into the extracellular space.…”

“…Cleavage of the cell adhesion protein E-cadherin enhances metastasis . In addition to their predominantly extracellular effects associated with cancer, intracellular proteolytic processes mediated by cysteine cathepsins have also been linked to tumor progression. , With regard to the particular function of cathepsin B in neoplastic diseases, the secretion of this cathepsin seems to be regulated by tumor-associated processes. Accordingly, the lower pH in the tumor microenvironment induces the relocation of cathepsin B-containing vesicles to the cell surface and the release of their content into the extracellular space. , Additionally, the enzyme is secreted by tumor-associated benign cells such as macrophages, fibroblasts, osteoclasts, T-lymphocytes, and endothelial cells. , The correlation between cathepsin B activity and the metastatic potential in B16 melanoma cells was demonstrated 40 years ago …”

A View on Cathepsin C as a Target for Therapy in AAV

“…The cathepsins, members of the large family of papain-like cysteine peptidases, have become the subject of intense research because of their increasingly well-defined roles in immune responses, both in homeostatic conditions and in autoimmunity and the host response to tumors 1 , 2 . Of particular note is the role of the endosomal/lysosomal aminopeptidase cathepsin C (CatC) in coordinating activation of serine proteases released from azurophilic granules of stimulated neutrophils 1 – 3 . These proteases, which include neutrophil elastase, proteinase 3 (PR3), and neutrophil serine protease 4 (NSP4), are an important defense against bacterial infection and collateral tissue injury 1 , 2 .…”

“…Of particular note is the role of the endosomal/lysosomal aminopeptidase cathepsin C (CatC) in coordinating activation of serine proteases released from azurophilic granules of stimulated neutrophils 1 – 3 . These proteases, which include neutrophil elastase, proteinase 3 (PR3), and neutrophil serine protease 4 (NSP4), are an important defense against bacterial infection and collateral tissue injury 1 , 2 . They are thought to be responsible for the hyperacute inflammation in the lung injury mediated by severe acute respiratory syndrome coronavirus 2 3 , 4 .…”