Review Article

A Critical Appraisal of Quantitative Studies of Protein Degradation in the Framework of Cellular Proteostasis

Figure 1

Schematic diagram of cell proteostasis. The boxes illustrate the different cellular process involved in protein homeostasis. BOX 1, nucleus, where gene transcription and pre-mRNA processing produce the mature mRNA that will be transported to the cytoplasm where it could be degraded (mRNA decay can also take place in the nucleus). The mRNA is engaged, mainly in the cytoplasm, to translation by the ribosomal machinery producing a nascent polypeptide that grows to a newly synthesized protein (BOX 2). The folding of the newly synthesized proteins, helped by chaperones, results in the “so-called” native protein structure either monomeric or oligomeric (BOX 3, only a dimer is shown for simplicity). Both the newly synthesized proteins and the mature mono or oligomeric forms of proteins are subjected to post-translational modification (PTM) and specific and unspecific protein-protein interactions (PPIs) that are illustrated in BOX 4. Proteins due to changes in its native conformation produced by different physical and/or chemical perturbations of the cell, or by mutations, could get misfolded or misprocessed and misfolded. The misfolded proteins, perhaps under the influence of PPIs and PTMs, will produce protein aggregates or soluble oligomeric protofibrils that eventually may form amyloid fibers (BOX 5). The degradation of proteins (BOX 6) is mainly due to the ubiquitin-proteasome System (UPS, nucleus and cytoplasm, 20S, and 26S proteasome) and the autophagic pathways (cytoplasmic): mainly chaperone-mediated authopagy (CMA) and macroautophagy (autophagy). Other proteases also participate in protein degradation (calpains, caspases, etc.), not shown. Blue lines connect all the boxes to the central circular box of protein degradation (BOX 6) indicating that proteolysis can regulate any of the process and vice versa. Black arrows connecting boxes indicate the “flow” of the products depicted in each BOX.
823597.fig.001