Stochastics of degradation: the autophagic-lysosomal system of the cell

Abstract

Autophagy is a conservative and evolutionarily ancient process that provides transfer of various cellular substances, organelles and potentially dangerous cellular components to the lysosome for their degradation. This process is crucial for the recycling of energy and substrates, which are required for the cellular biosynthesis. Autophagy plays a major role not only in the survival of cells under stress conditions, but also is actively involved in maintaining of cellular homeostasis. It has multiple effects on immune system and cellular remodeling during organism development. The effectiveness of autophagy is ensured by the tightly managed interaction of two organelles autophagosomes and lysosomes. Despite significant progress in description of molecular mechanisms underlying in autophagolysosomal system (ALS) functioning, many fundamental questions are still open. Namely, specialized functions of lysosomes and role of ALS in pathogenesis of human diseases are still enigmatic. Knowledge about mechanisms of subsequent stages of autophagolysosomal degradation, from the initiation of autophagy to the terminal stage of substrate destruction in the lysosome, may generate new approaches in order to orchestrate ALS and therefore selectively control cellular proteostasis.

Programmed cell death in cerebellar Purkinje neurons

“…Once the autophagosome is formed, its outer membrane completely fuses with the outer lysosomal membrane making a path for the autophagic body, which is the inner membrane-bound autophagic vacuole [77]. Thus, the autophagic body is released into the lysosomal cavity [78]. Then, contents of the autophagosome are degraded by the hydrolytic enzymes in the acidic lysosomal environment.…”

“…Mitochondria, lysosomes, and endoplasmic reticulum play a significant role in the discharge and activation of death factors, as summarized in Table 1 (Ref. [77][78][79][97][98][99][100][101][102][103][104][105][106][107][108]). Death factors are factors signaling and mediating death pathways such as cathepsins, calpains, and other proteases.…”

At the Cutting Edge against Cancer: A Perspective on Immunoproteasome and Immune Checkpoints Modulation as a Potential Therapeutic Intervention

“…In living cells, the proteome is constantly tuned through a complex, entwined, and multi-subcellular compartments network which coordinates the synthesis, folding, conformational upkeep and degradation of individual proteins [ 1 ]. The removal of undesired proteins is carried out by two main intracellular proteolytic systems, namely the ubiquitin–proteasome system (UPS) and autophagy [ 17 , 18 , 19 , 20 ]. The UPS is the major actor in the turnover of more than half of intracellular proteins that play fundamental roles in several facets of cell life, such as cell cycle, apoptosis, DNA repair, antigen presentation, inflammation, cellular response to environmental stress, and morphogenesis of neuronal networks [ 21 , 22 , 23 ].…”

“…Emerging evidence shows that a protein tagged with at least four ubiquitin molecules is not the unique signal for proteasome degradation by 26S: in fact, multiple or single monoubiquitination appears to be sufficient to label a substrate for proteasomal degradation [ 53 , 54 ]. Additionally, a series of proteins has been reported to be degraded by the 26S regardless of ubiquitination [ 20 , 55 , 56 ], implying the existence of alternative molecular signals, such as a specific amino acidic sequence or structural elements (also called “degrons”), that mediate substrate recognition and degradation [ 19 , 56 , 57 , 58 ]. An additional topic that underlines the complexity of proteasome degradation pathway is the ubiquitin-independent degradation of macromolecular substrates by the uncapped 20S: several studies demonstrate that the 20S degrades natively unfolded and oxidative stress-damaged proteins [ 15 , 59 , 60 , 61 ].…”

“…PA28αβ levels dramatically increase virtually in any other tissues in response to inflammatory stimuli, concomitant with the increase in other components of the MHC-I antigen processing pathway [ 120 , 134 ]. The i20S in association with PA28αβ mediates Ub-independent hydrolysis of the myelin basic protein during autoimmune neurodegeneration, accomplished through a novel class of charge-dependent proteasomal degrons [ 19 , 59 ].…”