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Ubiquitination (also known as ubiquitylation) is a form of post-translation modification (PTM) in which ubiquitin is attached to a target protein. Ubiquitin is a 76 amino acid protein that exists in the free form or can be conjugated to a protein as a single ubiquitin (ie, monoubiquitination)  or as a multiple ubiquitin (ie, polyubiquitination). Ubiquitination plays versatile roles in protein functions ranging from protein degradation to subcellular localization and kinase activation. Three enzymes are involved in the ubiquitination pathway: Ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3). Ubiquitination is highly relevant to the pathobiology of many human diseases. This review explores the fundamentals of ubiquitination, its function, pathophysiology, and clinical significance of ubiquitination.[1]

As discussed in previous sections, the ubiquitin-proteasome pathway is important in maintaining protein homeostasis and trafficking. Ubiquitination occurs throughout eukaryotic cell signaling and has been implicated in many malignancies through the gain of function and loss of function mutations. Loss of function mutation on the tumor suppressor gene can lead to inhibition or activation of ubiquitination. The gain of function mutations has mainly been implicated with increased activation of ubiquitination. In von-Hippel Lindau (VHL) disease, the loss of function mutation in the VHL tumor suppressor results in hemangioblastoma formation in multiple organs, renal cell carcinoma, and pheochromocytoma—the VHL tumor suppressor gene codes for the VHL protein. The VHL protein is an E3 ubiquitin ligase that catalyzes the ubiquitination of hypoxia-inducible transcription factor-alpha (HIF1-alpha). HIF-alpha regulates erythropoietin (EPO) production and vascular endothelial growth factor (VEGF). Under normal physiologic conditions, HIF1-alpha remains hydroxylated. In the hydroxylated form, it can be recognized and degraded by the VHL protein. This results in the prevention of EPO and VEGF induction under normoxic conditions. In VHL disease, the gene mutation results in the VHL protein’s inability to bind HIF-alpha, leading to uncontrolled growth. Another way ubiquitination has been implicated in malignancy is by how uncontrolled proliferation has evaded the ubiquitin-proteasome protein degradation pathway. The ubiquitin-proteasome system plays a vital role in colorectal cells in regulating the APC (adenomatous polyposis coli)/beta-catenin signaling pathway, which regulates the growth of colorectal epithelial cells. Mutations in APC fail to degrade beta-catenin, inhibiting cell proliferation.

Another way ubiquitination has been implicated in malignancy is by how uncontrolled proliferation has evaded the ubiquitin-proteasome protein degradation pathway. The ubiquitin-proteasome system plays a vital role in colorectal cells in regulating the APC (adenomatous polyposis coli)/beta-catenin signaling pathway, which regulates the growth of colorectal epithelial cells. Mutations in APC fail to degrade beta-catenin, inhibiting cell proliferation. Ubiquitination also correlates with several genetic disorders. Angelman syndrome is a rare genetic disorder affecting the nervous system that results from a mutation in UBE3A, which codes for an E3 ubiquitin ligase. Previous genetic studies have proposed that the UBE3A-encoded E3 ubiquitin ligase is important for normal human cognitive function. 3-M syndrome is a disorder characterized by intrauterine growth retardation that results from mutations in CUL7, which is important in assembling an E3 ubiquitin ligase complex and promoting ubiquitination. Disruption of this pathway plays a role in the pathogenesis of 3-M syndrome.[14][15][16][17]