The Aging of the Neuronal Cytoskeleton
Alvaro Macieira-Coelho in Molecular Basis of Aging, 2017
Just like MAP tau, ubiquitin appears as a common constituent of many cytological alterations of the cytoskeleton observed during aging and disease. Ubiquitin is a 76-residue protein which is found throughout the animal and plant kingdoms.96 This protein can be covalently conjugated to other intracellular proteins, a process that induces the selective proteolytic degradation of these protein-ubiquitin conjugates. However, some ubiquitin-protein conjugates are relatively stable, indicating that ubiquitin is also involved in regulatory processes more selective and specific than the destruction of defective proteins.97 In particular, ubiquitin seems to be associated with the microtubule network in certain cells.98 Several MAPs have been identified as the proteins carrying the ubiquitin tag in these microtubules.97,98 However, the principal proteins composing cytoskeletal alterations are not normally conjugated to ubiquitin.
Pathology, aetiology and pathogenesis
Jeremy Playfer, John Hindle, Andrew Lees in Parkinson's Disease in the Older Patient, 2018
Over the past few years a number of single-gene defects associated with parkinsonism have been described (seeTable 2.1). Where known, the protein products of these genes have been shown variously to be associated with abnormal protein accumulation and degradation, oxidative stress and mitochondrial dysfunction. An important mechanism of cellular damage emerging from this work appears to dysfunction of the ubiquitin-proteosome system (UPS). The UPS is essential for the degradation and clearance of misfolded and redundant proteins. Proteins are ‘labelled’ for degradation by becoming attached to chains of the protein ubiquitin. This is a three-stage enzymatic process. The polyubiquinated protein is then cleaved by the proteosome. The proteosome is a large multi-catalytic protease and is essential for cellular function. It protects the cell against oxidative stress and and prevents the accumulation of damaged or toxic proteins.
Cell structure, function and adaptation
C. Simon Herrington in Muir's Textbook of Pathology, 2020
The half-life of cellular proteins varies from seconds to months or years. The haemoglobin protein in red blood cells lasts for more than 100 days before the cell is removed from the circulation. The regulation of cellular proteins is a complex and important process for cell viability and function. If damaged protein accumulates it may inhibit normal protein function or injure the cell directly. Genetic abnormalities resulting in abnormal proteins are implicated in many diseases. In cystic fibrosis (see Chapter 8) a transmembrane chloride channel is dysfunctional, and this results in abnormal mucus secretion that leads to the phenotype seen clinically. In storage diseases, such as α1-antitrypsin disease, an abnormal protein is produced that cannot be efficiently secreted from the cell. The protein accumulates and can cause damage to the liver cells resulting in hepatitis, which may progress to cirrhosis (see Chapter 11). In addition, the absence of functional anti-protease in plasma leads to an increased risk of emphysema developing in the lungs (see Chapter 8). Mutation of tumour-suppressor genes can result in the formation of proteins with abnormal folding characteristics. Sometimes these inhibit the function of the corresponding normal protein (a dominant negative effect) and so contribute to the pathogenesis of cancer (see Chapter 6). Normally, damaged protein is marked for degradation by being bound to a carrier protein called ubiquitin, a process known as ubiquitination. This ubiquitinated protein is then removed from the cellular pool and degraded in the proteasome.
Cardiotoxicity of cancer chemotherapy in clinical practice
Published in Hospital Practice, 2019
In the cells, the damaged and unwanted proteins are degraded and removed by the proteasomal enzymes [66–69]. The proteins marked for degradation are first tagged with ubiquitin (named for its abundance in the cells). Ubiquitylation is essential for the recognition of proteins marked for degradation by the proteasomes. The ubiquitin-proteasome system is essential for proteostasis or the maintenance of an optimal protein level in the cells through a balance between synthesis and degradation. This system also permits the development of anticancer therapies. Bortizimib (Valcade™) and Carfilzomib (Kyprolis™) are proteasome inhibitors. Bortizimib has a boron atom in its structure, which binds and inactivates 26S proteasome. It prevents the proteasome from degrading the pro-apoptotic proteins, which actives apoptosis in the neoplastic cells that are dependent upon the suppression of proapoptotic pathways. This is used to treat multiple myeloma and mantle cell lymphoma. Cardiomyopathy has been observed in 2–4% of patients treated with this agent. Cardiac function should be monitored in the patients undergoing treatment with this agent.
The safety of bortezomib for the treatment of multiple myeloma
Published in Expert Opinion on Drug Safety, 2018
Guldane Cengiz Seval, Meral Beksac
Bortezomib (formerly known as PS-341) is a peptide boronic acid warhead containing a slowly reversible inhibitor of the β5 chymotrypsin-like subunit of the 20S proteolytic site of the 26S proteasome [6]. Although the mechanisms of its anticancer activity by proteasome inhibition are not fully clarified, it is clear that multiple mechanisms are involved. Proteins that are no longer required, including those recruited into the cell cycle control, DNA repair, apoptosis, and cell signaling, are labeled with ubiquitin that drive them to the proteasome which subsequently degrades them in all eukaryotic cells [7]. This process provides the balance of inhibitory and stimulatory proteins concerned in cell cycle, therefore inhibition of the proteasome results in a loss of the strict control of this process with an enhanced of cell cycle and regulatory proteins leading to cell death that contribute to onco-pathogenesis [8].
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.
Related Knowledge Centers
- Eukaryote
- Genome
- Proteasome
- Proteolysis
- Subcellular Localization
- Regulation of Gene Expression
- Ubiquitin C
- 40S Ribosomal Protein S27A
- Protein–Protein Interaction
- Ubiquitin-Activating Enzyme