Cells recognize and selectively degrade specific proteins within the cell through a highly regulated process called protein degradation. This process is essential for maintaining cellular homeostasis, controlling protein quality, and regulating various cellular processes. There are two major pathways involved in protein degradation: the ubiquitin-proteasome system UPS and the autophagy-lysosome pathway.1. Ubiquitin-Proteasome System UPS :The UPS is the primary pathway for selective degradation of short-lived, misfolded, or damaged proteins. The process involves three main steps:a Ubiquitination: This is the process of tagging target proteins with a small protein called ubiquitin. This tagging is carried out by a series of enzymes: E1 ubiquitin-activating enzyme , E2 ubiquitin-conjugating enzyme , and E3 ubiquitin ligase . The E3 ligase is responsible for substrate recognition and determines the specificity of the process.b Proteasome recognition: The polyubiquitinated proteins are recognized by the 26S proteasome, a large protein complex responsible for protein degradation. The 26S proteasome consists of a 20S catalytic core and two 19S regulatory particles. The 19S regulatory particles recognize the polyubiquitin chain and unfold the target protein.c Proteolysis: The unfolded protein is then translocated into the 20S catalytic core, where it is cleaved into small peptides by proteolytic enzymes. These peptides are further degraded into amino acids, which can be reused by the cell for protein synthesis.2. Autophagy-Lysosome Pathway:The autophagy-lysosome pathway is responsible for the degradation of long-lived proteins, protein aggregates, and damaged organelles. This pathway involves the formation of double-membrane vesicles called autophagosomes, which engulf the target proteins or organelles. The autophagosomes then fuse with lysosomes, forming autolysosomes. Lysosomes contain hydrolytic enzymes that degrade the engulfed material into its basic components, which can be recycled by the cell.There are three main types of autophagy:a Macroautophagy: This is the most common type of autophagy, where the autophagosome engulfs a portion of the cytoplasm, including the target proteins or organelles.b Microautophagy: In this process, the lysosomal membrane directly engulfs the target proteins or organelles.c Chaperone-mediated autophagy CMA : This is a selective form of autophagy, where specific proteins containing a KFERQ-like motif are recognized by a chaperone protein, Hsc70, and then translocated into the lysosome for degradation.Both the UPS and autophagy-lysosome pathways play crucial roles in maintaining cellular homeostasis and protein quality control. Dysregulation of these pathways has been implicated in various diseases, including neurodegenerative disorders, cancer, and immune system disorders.