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CBL Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Through its E3 ubiquitin ligase activity, the CBL protein mediates the transfer of ubiquitin from ubiquitin-conjugating enzymes (E2) to specific substrates, and interacts with and promotes tyrosine-phosphorylated substrates for proteasome degradation and ubiquitination. In experimental knockout mice, removal of the CBL gene prolongs activation of tyrosine kinases after cytokine stimulation, enhances sensitivity to hematopoietic growth factors, and expands hematopoietic stem cell pool and myeloproliferative features [16,17].
Proteasome and Protease Inhibitors
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
N. E. Franke, J. Vink, J. Cloos, Gertjan J. L. Kaspers
The ubiquitin-conjugating system targets proteins for degradation by attachment of poly-ubiquitin (Ub) chains (30). This ubiquitination is mediated by three enzyme families: E1, E2, and E3. The Ub-activating E1 enzyme binds and activates ubiquitin. The E2 and E3 families consist of many members. One of the Ub-conjugating enzymes E2 transfers the activated ubiquitin to an E3 family member, after which this E3 Ub ligase can mediate the attachment of Ub to the desired protein. By repeating this step, a Ub chain is formed (6). After the attachment of Ub chains to a protein, this protein binds to the subunits of the 19S complex, where it is de-ubiquitinated and subsequently unfolded. The Ub components can then be recycled. Following unfolding, the protein is processed to the 20S complex, where peptides of various lengths (3–22 amino acids) are formed (31,32).
Other Novel Targeted Therapies in Lung Cancer
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
Kyriakos P. Papadopoulos, Anthony W. Tolcher
Controlled protein degradation to maintain cell homeostasis is mediated by the ubiquitin-proteasome pathway (Fig. 2) (141). The ubiquitin-conjugating system targets proteins for degradation by attaching the activated ubiquitin polypeptide in a posttranslational modification known as ubiquitylation (142). Polyubiquinated proteins serve as the substrate for proteolysis by the proteasome core, a 20S mul-tisubunit structure of four stacked rings with a catalytic inner chamber. Among proteins degraded by the ubiquitin-proteasome pathway are those involved in apoptosis, cell cycle progression, and transcription (143). Exposure to IFN-γ results in exchange of low-molecular-weight protease subunits for constitutive beta subunits, modifies the cleavage specificities of the proteasome, and yields an immunoproteasome that is key to generating peptides for eventually bind to MHC class-I molecules (144). Ubiquination can also function as a signal for kinase activation and protein trafficking.
Negative Regulation of RIG-I by Tim-3 Promotes H1N1 Infection
Published in Immunological Investigations, 2023
Qingzhu Shi, Ge Li, Shuaijie Dou, Lili Tang, Chunmei Hou, Zhiding Wang, Yang Gao, Zhenfang Gao, Ying Hao, Rongliang Mo, Beifen Shen, Renxi Wang, Yuxiang Li, Gencheng Han
Compared to regulation at the transcription level, the post-translational modification of RIG-I plays a more important role in immunity against virus as it provides faster control. Ubiquitination is an important post-translational modification involved in various cellular functions (Jiang and Chen 2011). E3 ubiquitin ligases have been reported to play critical roles in the regulation of RIG-I activity (Kawai and Akira 2011; Medvedev et al. 2015). The E3 ubiquitin ligase tripartite motif containing protein 25 (TRIM25), Riplet (also known as RNF135), and MEX3C deliver the K63-linked polyubiquitin moiety to RIG-I CARDs and the C-terminal domain, thus positively regulating RIG-I-mediated signaling (Gack et al. 2007; Kuniyoshi et al. 2014; Oshiumi et al. 2010). However, RING E3 ligase RNF122 and RNF125 mediate K48-linked ubiquitination of RIG-I, leading to RIG-I degradation by proteasomes, thus negatively regulating RIG-I-mediated signaling (Arimoto et al. 2007; Wang et al. 2016). Here, we found a direct interaction and co-localization between Tim-3 and RIG-I, which inspired us to investigate the mechanisms by which Tim-3 regulates RIG-I. Furthermore, we also found that Tim-3 promotes RIG-I degradation through the ubiquitin-proteasome system. RNF122, an E3 ubiquitin ligase involved in proteasome-mediated degradation of proteins, plays a critical role in the K48-linked ubiquitination of RIG-I enhanced by Tim-3. These findings demonstrate that Tim-3 interacts with RIG-I and induces proteasomal degradation of RIG-I through RNF-122.
Human carbonic anhydrases and post-translational modifications: a hidden world possibly affecting protein properties and functions
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Anna Di Fiore, Claudiu T. Supuran, Andrea Scaloni, Giuseppina De Simone
Protein ubiquitinylation is a PTM in which the polypeptide ubiquitin is covalently added to K residues115. This reaction is catalysed by a number of E3 ligases, each of which transfers ubiquitin to corresponding protein targets. Depending on the addition of poly- or mono-ubiquitin chain, different effects are exerted on target proteins. In particular, addiction of ubiquitin polymerised through K48 residue acts as a signal targeting proteins for proteasomal degradation. Conversely, addiction of a poly-ubiquitin chain linked through other K residues can alter protein subcellular localisation or interactions. The latter effects are also exerted by mono-ubiquitinylation on target proteins. Ubiquitinylation is often targeted to newly synthesised proteins, which are highly susceptible to misfolding and aggregation. This PTM-based quality control ensures that misfolded proteins undergo proteasomal degradation. Ubiquitinylation sites on nascent misfolded proteins act as valuable biomarkers of cellular states, in which protein synthesis and/or folding has been disrupted, as observed in Alzheimer’s and Parkinson’s disease115. In response to signalling or other pathways, properly folded proteins can be also subjected to regulatory ubiquitinylation, which can influence protein functions and localisation.
Ubiquitin Associated and SH3 Domain Containing B (UBASH3B) Gene Association with Behcet’s Disease in Iranian Population
Published in Current Eye Research, 2019
Elham Shahriyari, Mortaza Bonyadi, Mohammad Hossein Jabbarpoor Bonyadi, Masoud Soheilian, Mehdi Yaseri, Nazanin Ebrahimiadib
Ubiquitination as a post-translational mechanism plays an important role in various biological processes, such as immune functions through modulating endocytosis and degradation of activated receptors. Invalid regulation of ubiquitination is attendant with autoimmune and inflammatory diseases.14,15 T cells as crucial component of acquired immunity are activated by intervention of their receiver.16 The UBASH3B (ubiquitin associated and SH3 domain containing B) gene, a component of the ubiquitin messenger genes, is involved in the negative regulation of signaling pathways downstream of the T cell receptor. UBASH3B has a unique multi-domain structure among ubiquitin messengers.17 The association of BD and rs4936742 UBASH3B polymorphism was initially reported in genome wide association study (GWAS) in Turkish population. Fei et al. in this study have suggested that the disease-associated polymorphism of UBASH3B rs4936742 may predispose to eye involvement in their cohort’s.18 In the present study, we investigated the possible association of rs4936742 UBASH3B gene polymorphism with BD and its manifestations among Iranian patients.