Other Novel Targeted Therapies in Lung Cancer
Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo in Lung Cancer, 2016
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.
Introduction to Cell Biology
Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George in The Scientific Basis of Urology, 2010
Another key posttranslational modification is ubiquitylation, a process whereby a small molecular weight protein called ubiquitin is covalently attached to lysine residues on a target protein (Fig. 4B). This is achieved by the sequential action of ubiquitin-activating (E1), ubiquitin-conjugating (E2), and ubiquitin-ligating (E3) enzymes. The mechanism of ubiquitylation is analogous to phosphorylation in that it can be activated by cell surface ligands, is reversible, and can determine protein-protein interactions. However, unlike phosphorylation, multiple types of ubiquitylation can occur, rendering it a more complex system. Ubiquitin can be ligated as a single molecule (monoubiquitylation) or as a polymeric chain (polyubiquitylation). The biological effects of different forms of ubiquitylation are diverse, but the best characterized is endocytosis. In this process, transmembrane proteins tagged with ubiquitin are internalized by the cell into a vesicle known as endosome. The type of ubiquitylation then determines whether the protein is recycled back to the membrane, or whether it proceeds to the lysosome where it is degraded into its constituent amino acids. Ubiquitylation can also play a role in the nucleus, for example, by decreasing the stability of transcription factors, and in DNA repair pathways.
Proteasome and Protease Inhibitors
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
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).
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.
Increased expression of Triad1 is associated with neuronal apoptosis after intracerebral hemorrhage in adult rats
Published in International Journal of Neuroscience, 2020
Shuyao Wang, Feng Xue, Wanyan Li, Yisi Shan, Xingxing Gu, Jiabing Shen, Kaifu Ke
Ubiquitin modification of proteins is very important in several cellular functions, including protein degradation, cycle regulation, cell growth and apoptosis [12]. Ubiquitination enzymes can divided into three parts: E1 activating enzyme, E2 conjugating enzyme and E3 ligase enzyme [13]. TRIAD contains a cysteine-rich DRIL/IBR structure which binds K48 chain E2 conjugating enzyme through its N-terminal RING finger, and connects with K63 E2 enzyme through the C-terminal RING finger [14, 15]. Triad1 belongs to TRIAD family, and can bind to UbcH7 and Ubc13 of E2 ubiquiting-conjugating enzyme to catalyze the formation of different polyubiquitin chains in previous studies [16, 17]. Furthermore, p53 takes part in cell differentiation, cell cycle arrest, and senescence, especially apoptosis [18, 19]. Moreover, previous study has indicated that Triad1 is a novel E3 ligase protein that can induce apoptosis of several cancer cells through p53 activation [20]. However, the function of Triad1 in ICH remains unknowing. Therefore, it is necessary to explore the function of Triad1 on neuronal apoptosis after ICH.
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.
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