**4. Protein Quality Control**

Eukaryotic cells possess a robust complement of proteins to monitor and maintain a healthy proteome for their survival. Proteome integrity is maintained under the scrutiny of the PQC system [47]. The maturation from a nascent polypeptide to a functional protein is crucial to its function and involves a multistep process, including proper post-translational modification. The folding process for some proteins starts during their synthesis itself, which is called co-translational folding, whereas other proteins fold in the cytoplasm or the endoplasmic reticulum (ER) and mitochondria after synthesis [48]. The fundamentals of protein folding are also governed by the cellular environment and its over-crowding [49]. The hydrophobic patches in a polypeptide are buried in the native state. Exposure leads to the formation of intermediates that can interact inappropriately with other molecules. Thus, several studies sugges<sup>t</sup> that protein folding is initiated by composing a folding nucleus within a primary structure around which the remaining polypeptide folds. The most important requirement for a correct folding pattern is the interaction between the hydrophobic and polar residues during nucleation, which encourages the structure to be packed correctly [50].

The protein-folding mechanism is much more complex for larger proteins than for smaller ones. Evidence from various studies indicates that, during protein folding, some proteins attain the native structure, whereas others cannot, for reasons such as a non-native interaction that leads to intermediates or a transiently folded protein state. Therefore, large proteins are assembled from diverse segments or domains that are folded simultaneously and independently, ensuring the proper folding of each segment, so that they can correctly interact with one another to form a highly stable and compact, native, three-dimensional protein structure. In other words, for large protein complexes such as proteasomes and ribosomes, the folding pathway involves a two state mechanism [51,52].

The ability of a protein to fold correctly de novo, though thermodynamically favorable, is often hampered by transcriptional or translational errors, destabilizing mutations, or stress conditions such as heat, oxygen radicals, aging, or environmental threats, giving rise to misfolded proteins and o ff-pathway aggregates [53–55]. The misfolded proteins can exhibit either loss of function, characterized by protein dysfunction and a propensity for degradation, or gain of function, characterized by protein aggregates that cause the misfolding of other proteins through inappropriate interactions [50,56]. Cells are rescued from the dangers of misfolded proteins by the PQC system, which keeps proteins under the constant surveillance of molecular chaperones and induces the rapid degradation of misfolded proteins through the UPS or autophagy-driven lysosomal proteolysis [57,58] (Figure 1). PQC relies on three parallel strategies whereby misfolded proteins are refolded, degraded, or delivered to a quality-control compartment capable of sequestering them, such as the juxta nuclear quality control, insoluble protein deposit, aggresome, or ER-associated degradation (ERAD) vesicles [48].
