Ubiquitin constitutes a highly conserved 76-amino acid regulatory protein prevalent in eukaryotic organisms. This small polypeptide facilitates substrate modification through sequential enzymatic activation by E1, E2, and E3 ligases, directing tagged proteins toward 26S proteasome-mediated degradation. Its covalent conjugation system governs critical cellular functions encompassing cell cycle regulation, DNA repair mechanisms, and inflammatory signaling pathways. The universal β-grasp fold architecture enables ubiquitin's recognition by proteasomal receptors and deubiquitinating enzymes across species. Initially isolated during biochemical investigations of ATP-dependent proteolysis in the 1970s, ubiquitin became the first post-translational modifier characterized through X-ray crystallography. Structural analyses revealed conserved lysine residues (K29, K48, K63) dictating polyubiquitin chain topology and functional specificity. Ubiquitination research has established fundamental principles of protein homeostasis, with mechanistic insights driving therapeutic strategies for cancer and neurodegenerative diseases. Current pharmacological approaches target specific E3 ligases and deubiquitinases, modulating substrate stability through precision intervention in ubiquitin signaling cascades.
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Fig. 1 OtDUB1–259–ubiquitin crystal complex reveals three distinct ubiquitin-binding sites.1
Ubiquitin operates as a universal regulatory molecule orchestrating critical cellular processes through dynamic post-translational modifications. Its functional spectrum spans three principal dimensions of biological control:
This multifunctional modification system integrates cellular metabolism, genomic stability, and stress responses, establishing ubiquitination as a master switch governing cellular fate determination and therapeutic intervention.
1. Chipumuro, Edmond, and Melissa A Henriksen. "The ubiquitin hydrolase USP22 contributes to 3'-end processing of JAK-STAT-inducible genes." FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26.2 (2012): 842-54. https://doi.org/10.1096/fj.11-189498
This study reveals that dynamic ubiquitination of histone H2B (ubH2B) governs transcriptional elongation and mRNA 3'-end processing in JAK-STAT signaling, identifying the deubiquitinase USP22 as a pivotal regulator coordinating RNA polymerase II phosphorylation and polyadenylation factor recruitment. The established H2B ubiquitination/deubiquitination cycle provides mechanistic insights into USP22's dual role in maintaining transcriptional fidelity and its potential as a therapeutic target for cancers with dysregulated STAT-dependent gene expression.
2. Whitcomb, Elizabeth A, and Allen Taylor. "Ubiquitin control of S phase: a new role for the ubiquitin conjugating enzyme, UbcH7." Cell division 4.17 (2009). https://doi.org/10.1186/1747-1028-4-17
This study identifies UbcH7 as a critical ubiquitin-conjugating enzyme regulating S-phase progression through the PTEN/Akt/Chk1 axis, revealing its dual mechanism in controlling cell cycle checkpoints and DNA replication fidelity via ubiquitin-dependent proteolysis. The findings establish UbcH7-mediated ubiquitination as a novel regulatory node coordinating proliferation dynamics and genomic stability in eukaryotic cell division.
3. Bergamaschi, Anna et al. "The human immunodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1 DCAF1 ubiquitin ligase to overcome a postentry block in macrophage infection." Journal of virology 83,10 (2009): 4854-60. https://doi.org/10.1128/JVI.00187-09
This study elucidates that the HIV-2/SIVsm accessory protein Vpx hijacks the CUL4A-DDB1 ubiquitin ligase complex via DCAF1 recruitment to degrade host restriction factors, and identifies this ubiquitin-dependent proteolytic mechanism as the molecular basis for viral replication specificity in macrophages, resolving the long-standing paradox of HIV-1 macrophage infectivity without Vpx.
4. Fryrear, Kimberly A et al. "The Sumo-targeted ubiquitin ligase RNF4 regulates the localization and function of the HTLV-1 oncoprotein Tax." Blood 119,5 (2012): 1173-81. https://doi.org/10.1182/blood-2011-06-358564
This study demonstrates that the SUMO-targeted ubiquitin ligase RNF4 mediates ubiquitination-dependent nuclear export of the HTLV-1 Tax oncoprotein, and identifies this STUbL-mediated relocalization as a novel regulatory switch that differentially modulates NF-κB and CREB signaling pathways to control viral oncogenesis.
5. Sun, Fan et al. "PDLIM2 is a novel E5 ubiquitin ligase enhancer that stabilizes ROC1 and recruits the ROC1-SCF ubiquitin ligase to ubiquitinate and degrade NF-κB RelA." Cell & bioscience 14.1 (2024):99. https://doi.org/10.1186/s13578-024-01281-x
This study reveals that the tumor suppressor PDLIM2 functions as a ubiquitin ligase enhancer (E5) by stabilizing the ROC1-SCFβ-TrCP complex to mediate nuclear RelA ubiquitination, and identifies this chromatin-bound ubiquitination cascade as a novel therapeutic target for cancers driven by persistent NF-κB activation and inflammatory pathogenesis..
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