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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
As cells continuously produce proteins throughout their lifetime, they have also evolved mechanisms to destroy them and recycle the constituent amino acids. It is particularly important that cells can destroy signaling proteins, as otherwise many signaling pathways would be in a permanently “on” state (or “off” state for an inhibitory pathway). The principal route for the degradation of proteins (including signaling proteins) within cells is the ubiquitin-proteasome pathway (Figure 6.80). Proteins destined for degradation are initially “tagged” with a polyubiquitin chain. The tagged protein is then recognized by the proteasome, a large multimeric protein found within all eukaryotic cells, which degrades it to the constituent peptides and free ubiquitin units.
Modulating Cytolytic Responses to Infectious Pathogens
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Rebecca Pogue Caley, Jeffrey A. Frelinger
Major histocompatibility complex class I restricted antigen presentation primarily involves the MHC class I heavy chain binding peptides which have been generated within the cytoplasm of the cell. Several lines of evidence implicate the proteasome as involved in this degradation of cytosolic proteins for antigen presentation. First, genes encoding for two of the proteasome’s subunits, low-molecular-weight protein (LMP)-2 and LMP-7, are located within the MHC class II region [2,3]. Second, the proteasome is involved in both ubiquitin-dependent and ubiquitin-independent protein degradation pathways within the cell. Third, inhibitors of proteasome function, such as dipeptide aldehydes, can block the presentation of model peptides [4].
Molecular Pathology
Published in Burkhard Madea, Asphyxiation, Suffocation,and Neck Pressure Deaths, 2020
Ubiquitin is a highly conserved protein in all eukaryotes, and it seems to be involved in neurodegenerative diseases and damage induced by chronic ischaemia. Immunohistochemically, ubiquitin was localized at the nuclei of pigmented substantia nigra neurones, with two staining patterns − inclusion and diffuse types. In particular, both staining patterns were more evident in mechanical asphyxiation (strangulation and aspiration/choking) except for hanging and drowning strangulation, aspiration/choking and drowning. Collectively, intranuclear ubiquitin immunoreactivity of the pigmented substantia nigra neurones in the midbrain appear to be a hallmark in asphyxiation and drowning [22].
Open resources for chemical probes and their implications for future drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Esra Balıkçı, Anne-Sophie M. C. Marques, Jesper S. Hansen, Kilian V. M. Huber
Ubiquitination is the second most observed posttranslational modification in human proteins [70]. This process involves the cooperative activity of E1, E2, and E3 enzymes to tag protein substrates with ubiquitin chains to induce their proteasomal degradation. Components of the ubiquitin system are attractive therapeutic targets since aberrations in this process have been associated with many diseases such as cancer and neurodegeneration [71,72]. Several UPS-targeting small molecules have been approved or are undergoing clinical trials (see literature for relevant reviews, such as [73]). The best characterized E3 ligase modulators include thalidomide and its derivatives lenalidomide and pomalidomide, also called immunomodulatory drugs (ImiDs), which are approved for the treatment of multiple myeloma. These compounds enable surface remodeling of the E3 ligase substrate receptor cereblon (CRBN), altering its affinity for preferred substrates. Subsequent modifications to these so-called molecular glues yielded compounds with greater selectivity and a broader range of compatible substrates [74–76]. Aside from their therapeutic value, these drugs have paved the way for the emerging area of targeted protein degradation (TPD), highlighting the vast potential of proximity-induced pharmacology [77–79].
The role of E3 ubiquitin ligase in multiple myeloma: potential for cereblon E3 ligase modulators in the treatment of relapsed/refractory disease
Published in Expert Review of Proteomics, 2022
Paul G Richardson, María-Victoria Mateos, Annette J Vangsted, Karthik Ramasamy, Niels Abildgaard, P Joy Ho, Hang Quach, Nizar J Bahlis
The two main steps of the UPS are ubiquitin conjugation and proteasomal degradation (Figure 1) [29,31]. Target proteins are marked for degradation by the covalent attachment of multiple ubiquitin molecules to lysine residues in the protein. Polyubiquitin chains are recognized by 26S proteasomes for degradation. After proteolysis by the proteasome, target proteins are reduced to short peptides and ubiquitin molecules are released by deubiquitinating enzymes (DUBs) for reuse. Cereblon is a 442-residue protein that forms part of the cullin 4-based E3 ligase complex known as CRL4CRBN [32,33]. Cereblon binds to the DNA damage-binding protein 1 (DDB1) subunit of the complex, which also consists of a cullin 4 scaffold protein (CUL4A or CUL4B) and the E2-interacting protein regulator of cullins 1 (ROC1, also known as RING-box protein 1 [RBX1]). Cereblon allows the tagging of polyubiquitin chains to target proteins and serves as a substrate receptor in the E3 ligase complex for the target proteins [32,33]. The UPS recognizes substrates via degradation signals called degrons. Degrons can be divided into two main groups: acquired degrons, which are obtained via post-translational modifications such as phosphorylation or hydroxylation; and inherent degrons, which are formed by specific amino acid sequences or the structural arrangement of the protein [34]. In the presence of CELMoD compounds, cereblon can recognize structural degrons in neosubstrates such as Ikaros and Aiolos [21,35,36].
Targeting USP11 may alleviate radiation-induced pulmonary fibrosis by regulating endothelium tight junction
Published in International Journal of Radiation Biology, 2022
Yiting Tang, Qian Yuan, Congzhao Zhao, Ying Xu, Qi Zhang, Lili Wang, Zhiqiang Sun, Jianping Cao, Judong Luo, Yang Jiao
It is now evident that Ubiquitin-dependent signaling regulates post-replication repair and numerous ubiquitin ligating enzyme and deubiquitinating enzymes are differentially expressed in RIPF tissue (Roque et al. 2020). Previous studies have established that USP11 enhanced the TGF-β signaling pathway which is the impact for the progression of RIPF, we further explored the role of USP11 in RIPF. IHC staining demonstrated that increased USP11 was expressed in RIPF tissues (Figure 1(A)). Double color immunofluorescence was performed to classify which type of cells USP11 dominating expressed in lung tissues. Our results showed that USP11 is commonly found in the endothelial cells (CD31 positive) and fibroblasts (a-SMA positive) (Figure S2). We then evaluated the expression of USP11 in the HELF, HuVEC, and HMEC-1 cells after irradiation. Accordingly, we found that USP11 was overexpressed in a dose-dependent manner (Figure 1(B)). These data indicate that USP11 dysfunction in RIPF which may promote pulmonary fibrosis development.