In this work, we firstly proposed a structural network as a tool to get an in-depth into complex biological systems. The concept was exemplified on the kallikrein-kinin and the renin-angiotensin systems (KKS-RAS), two highly regulated proteolytic systems involved in many physiological and pathological processes in which participate lysosomal cathepsins, including cathepsin F, among others which all belong to peptidase C1 family. All domain interactors up to level 4 were retrieved, displaying a more comprehensive representation of the studied system at atomic resolution.
COBISS.SI-ID: 23522087
In this work, we proposed the mechanism of action of cysteine cathepsins in various cellular models, after lysosomal disruption by LeuLeuOMe. Following lysosomal membrane permeabilization, the released cathepsins cleave the proapoptotic Bcl-2 family member Bid and degrade the antiapoptotic members Bcl-2, Bcl-xL, or Mcl-1, thus followed by mitochondrial damage. Moreover, the X-chromosome-linked inhibitor of apoptosis (XIAP) was also found to be a target of cysteine cathepsins, thus suggesting that cysteine cathepsins can mediate caspase-dependent apoptosis, also downstream of mitochondria.
COBISS.SI-ID: 21719335
Lysosomal proteases were found to participate in cell death pathways, which at least, during apoptosis, are suicidal for the cells. However, more recently, it became clear that the endosomal/lysosomal system has other roles, thus including survival functions. This work provides a current view on the role of the lysosomes, thus highlighting its involvement in cell survival.
COBISS.SI-ID: 22640935
We investigated the cell death - apoptosis, in two tumor-cell lines, U937 and T98G, thus induced by the tumor necrosis factor (TNF)-alpha. The cell death involved lysosomal destabilization and the release of cathepsins into the cytosol. However, the blockage of cysteine cathepsins with E64d and CA-074Me, had no effect on the progression of apoptosis in neither cell line, suggesting that TNF-alpha apoptosis is not critically dependent on cysteine cathepsins in these cellular models. This work is part of PhD thesis of Martina Klarić who worked in this project (experimental part is completed).
COBISS.SI-ID: 22717479
Lysosomal cysteine cathepsins represent a major group among cysteine proteases. In the human genome are present 11 enzymes, namely cathepsins B, H, L, S, C, F, K, O, V, W in X. In this article we review their features, structure, specificity and mechanism of inhibition by their endogenous inhibitors cystatins and thyropins. Their importance under physiological and pathological conditions is highlighted.
COBISS.SI-ID: 22321703