Deciphering Key Regulatory Roles of Linear Ubiquitination in Cell Fate Determination and Disease

Cell fate determination is a complex and dynamic process. Across diverse cellular contexts, various protein modifications (PTMs) are involved throughout the entire process of cell fate determination. Linear ubiquitination is a specific type of PTM. Under the catalysis of linear ubiquitin chain assembly complex, multiple ubiquitin molecules form a unique linear ubiquitin chain and modify the substrate. A growing number of studies have shown that linear ubiquitination is an important regulatory target in the cell fate determination pathway, and that once the linear ubiquitination process of key proteins is defective, the cell fate determination process will be disrupted and lead to the development of various diseases. In this review, we systematically elaborated the key links between linear ubiquitination and cell fate determination from the aspects of cell proliferation, differentiation, senescence, and survival/death. Furthermore, we provide an in-depth exploration of the molecular mechanisms through which homeostatic imbalance of linear ubiquitination contributes to numerous diseases, including neoplastic, neurodegenerative, infectious, inflammatory, and metabolic disorders. Finally, we fully affirm the significance of linear ubiquitination as a promising therapeutic target for future drug discovery and development. Our critical appraisal and synthesis of the literature provide a foundational framework for future investigations and inform novel strategies for the treatment and management of related diseases.