Chapter 1. Ubiquitin-Dependent Proteolysis, a Therapeutic Strategy: An Interface between Health and Disease


Rajiv Kumar¹,², Magali Cucchiarini³, Madan Thangavelu⁴, Moganavelli Singh⁵ and Punit Dhar⁶
¹University of Delhi, Delhi, India
²NIET, National Institute of Medical Science, India
³Center of Experimental Orthopaedics, Saarland University Medical Center and Saarland University, Homburg/Saar, Germany
⁴Single Cell & Single Molecule Genomics, Genome Mapping & Analysis Biotechnology, Cambridge, UK
⁵Nano-Gene and Drug Delivery Laboratory, Dept. of Biochemistry, School of Life Sciences, University of KwaZulu-Natal (Westville Campus), Durban, South Africa
⁶Department of Surgical Gastroenterology, AIIMS, Rishikesh, Uttarakhand, India

Part of the book: Advances in Health and Disease. Volume 63


All eukaryotic cells have a system in place called the ubiquitin-dependent proteolysis system to control protein degradation; nevertheless, any flaws in this system can initiate numerous fatal diseases, including cancer, metabolic problems, neurological disorders and diseases. These health complications interlink with faults in ubiquitin-dependent proteolysis. Ubiquitin assists as a post-translational targeting signal for altering the structure, localization of other proteins, features and functioning styles of the cells and tissues. The ubiquitin ligase standardizes the specific nature of the ubiquitination features and cellular response. The ubiquitin ligase is a critical element of the enzymatic cascade that regulates the part of the multipubiquitin chain to the target or labile protein. Consequently, the attachment of the ubiquitin topology is crucial for regulating healthy growth, differentiation, and protection of cells from damage by xenobiotics, infections, mutations, and environmental stresses. Protein degradation is adopted by the cells as a route to enduringly deactivate proteins. The 26S proteasome is responsible for ATP-dependent protein failure in the cytoplasm and nuclei of eukaryotes. Most proteins are covalently associated with a multi-ubiquitin chain and engage the 26S proteasome. In the testes, the ubiquitin ligases E1, E2, E3, and UBC4 are dynamic. Here, prompt and large protein alterations are essential for a cell to respond to its environment, and a complex web of interrelated events, including control over synthesis, localization, and degradation. The regulator of the cell cycle, receptor processing, growth management, and stress response are all subject to intracellular proteolysis. This chapter focuses on (I) the significant contribution of ubiquitination in the cellular signaling pathways that contract with these external influences; (II) the mechanisms of ubiquitination-deubiquitination that offer the system its high level of selectivity, (III) the role of ubiquitin-dependent degradation in initiating diseases in humans and forthcoming clinical claims developed to employ the cell’s built-in proteolytic machinery to cure diseases; (IV) to examine imaginable clinical practices fashioned to exploit the body’s own proteolytic machinery to cure the diseases, and analyze the effectiveness of vaccinations, antibodies, and other possible therapies that aim to block SARS-CoV-2 entrance pathways. Lastly, the authors include the most important unanswered queries pertaining to this crucial route.

Keywords: ubiquitin-dependent proteolysis, protein degradation, mechanisms of ubiquitination-deubiquitination, enzyme cascade, interface between health and disease


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