Protein degradation and turnover are essential processes in a cell, ensuring that proteins are maintained at appropriate levels, damaged proteins are removed, and cellular resources are efficiently utilized. The two primary mechanisms involved in protein degradation are the ubiquitin-proteasome system UPS and autophagy-lysosome pathway.1. Ubiquitin-Proteasome System UPS : The UPS is responsible for the selective degradation of most short-lived and abnormal proteins in the cell. The process involves three main steps: a. Ubiquitination: Target proteins are tagged with multiple ubiquitin molecules, a small regulatory protein. This process is carried out by three types of enzymes: ubiquitin-activating enzyme E1 , ubiquitin-conjugating enzyme E2 , and ubiquitin ligase E3 . The E3 ligase is responsible for substrate specificity, ensuring that only the correct proteins are targeted for degradation. b. Recognition and unfolding: The 26S proteasome, a large protein complex, recognizes the polyubiquitinated protein. The 19S regulatory particle of the proteasome binds to the ubiquitin chain and unfolds the target protein, preparing it for degradation. c. Proteolysis: The unfolded protein is translocated into the 20S core particle of the proteasome, where proteases cleave the protein into small peptides. The peptides are then released and further degraded into amino acids, which can be reused by the cell.2. Autophagy-Lysosome Pathway: This pathway is responsible for the degradation of long-lived proteins, protein aggregates, and organelles. There are three types of autophagy: a. Macroautophagy: This process involves the formation of a double-membrane structure called an autophagosome, which engulfs the target protein or organelle. The autophagosome then fuses with a lysosome, forming an autolysosome. The lysosomal enzymes degrade the contents, and the resulting amino acids and other components are released back into the cytosol. b. Microautophagy: In this process, the lysosomal membrane directly engulfs a small portion of the cytosol containing the target protein. The protein is then degraded by lysosomal enzymes. c. Chaperone-mediated autophagy CMA : This process is selective for specific proteins containing a KFERQ-like motif. Chaperone proteins recognize this motif and deliver the target protein to the lysosome, where it is translocated across the lysosomal membrane and degraded by lysosomal enzymes.In normal conditions, these mechanisms work together to maintain cellular protein homeostasis. However, under aberrant conditions such as oxidative stress, protein misfolding, or mutations, the protein degradation machinery may become overwhelmed or dysfunctional, leading to the accumulation of damaged proteins and aggregates. This can contribute to the development of various diseases, including neurodegenerative disorders like Alzheimer's, Parkinson's, and Huntington's disease, as well as certain types of cancer. Understanding the mechanisms of protein degradation and turnover is crucial for developing therapeutic strategies to target these diseases.