Ubiquitination and SUMOylation: protein homeostasis control over cancer

Epigenomics ◽  
2021 ◽  
Author(s):  
Xiaofeng Dai ◽  
Tongxin Zhang ◽  
Dong Hua

Ubiquitination and SUMOylation are two essential components of the ubiquitination proteasome system playing fundamental roles in protein homeostasis maintenance and signal transduction, perturbation of which is associated with tumorigenesis. By comparing the mechanisms of ubiquitination and SUMOylation, assessing their crosstalk, reviewing their differential associations with cancer and identifying unaddressed yet important questions that may lead the field trend, this review sheds light on the similarities and differences of ubiquitination and SUMOylation toward the improved harnessing of both post-translational modification machineries, as well as forecasts novel onco-therapeutic opportunities through cell homeostasis control.

2019 ◽  
Vol 23 (15) ◽  
pp. 1663-1670 ◽  
Author(s):  
Chunyan Ao ◽  
Shunshan Jin ◽  
Yuan Lin ◽  
Quan Zou

Protein methylation is an important and reversible post-translational modification that regulates many biological processes in cells. It occurs mainly on lysine and arginine residues and involves many important biological processes, including transcriptional activity, signal transduction, and the regulation of gene expression. Protein methylation and its regulatory enzymes are related to a variety of human diseases, so improved identification of methylation sites is useful for designing drugs for a variety of related diseases. In this review, we systematically summarize and analyze the tools used for the prediction of protein methylation sites on arginine and lysine residues over the last decade.


2021 ◽  
Vol 22 (9) ◽  
pp. 4728
Author(s):  
Tanuza Das ◽  
Eun Joo Song ◽  
Eunice EunKyeong Kim

Ubiquitination and deubiquitination are protein post-translational modification processes that have been recognized as crucial mediators of many complex cellular networks, including maintaining ubiquitin homeostasis, controlling protein stability, and regulating several signaling pathways. Therefore, some of the enzymes involved in ubiquitination and deubiquitination, particularly E3 ligases and deubiquitinases, have attracted attention for drug discovery. Here, we review recent findings on USP15, one of the deubiquitinases, which regulates diverse signaling pathways by deubiquitinating vital target proteins. Even though several basic previous studies have uncovered the versatile roles of USP15 in different signaling networks, those have not yet been systematically and specifically reviewed, which can provide important information about possible disease markers and clinical applications. This review will provide a comprehensive overview of our current understanding of the regulatory mechanisms of USP15 on different signaling pathways for which dynamic reverse ubiquitination is a key regulator.


2006 ◽  
Vol 34 (6) ◽  
pp. 1295-1298 ◽  
Author(s):  
Y.-J. Lee ◽  
J.M. Hallenbeck

Progression of acute ischaemic brain damage is complex and multifactorial. Also, evidence suggests that participating molecules and signal transduction pathways can function differently in different cellular contexts. Hibernation torpor, a model of natural tolerance to profoundly reduced blood flow and oxygen delivery to brain, along with models of induced ischaemic tolerance can guide efforts to identify cytoprotective mechanisms that are multifactorial and that target multiple mechanisms in multiple cellular contexts. Post-translational modification of proteins by conjugation with the SUMO (small ubiquitin-related modifier) is massively increased in hibernation and may be such a mechanism.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jessica Spagnolo ◽  
Mylaine Breton ◽  
Martin Sasseville ◽  
Carine Sauvé ◽  
Jean-François Clément ◽  
...  

Abstract Background In 2016, Quebec, a Canadian province, implemented a program to improve access to specialized health services (Accès priorisé aux services spécialisés (APSS)), which includes single regional access points for processing requests to such services via primary care (Centre de répartition des demandes de services (CRDS)). Family physicians fill out and submit requests for initial consultations with specialists using a standardized form with predefined prioritization levels according to listed reasons for consultations, which is then sent to the centralized referral system (the CRDS) where consultations with specialists are assigned. We 1) described the APSS-CRDS program in three Quebec regions using logic models; 2) compared similarities and differences in the components and processes of the APSS-CRDS models; and 3) explored contextual factors influencing the models’ similarities and differences. Methods We relied on a qualitative study to develop logic models of the implemented APSS-CRDS program in three regions. Semi-structured interviews with health administrators (n = 9) were conducted. The interviews were analysed using a framework analysis approach according to the APSS-CRDS’s components included in the initially designed program, Mitchell and Lewis (2003)’s logic model framework, and Chaudoir and colleagues (2013)’s framework on contextual factors’ influence on an innovation’s implementation. Results Findings show the APSS-CRDS program’s regional variability in the implementation of its components, including its structure (centralized/decentralized), human resources involved in implementation and operation, processes to obtain specialists’ availability and assess/relay requests, as well as monitoring methods. Variability may be explained by contextual factors’ influence, like ministerial and medical associations’ involvement, collaborations, the context’s implementation readiness, physician practice characteristics, and the program’s adaptability. Interpretation Findings are useful to inform decision-makers on the design of programs like the APSS-CRDS, which aim to improve access to specialists, the essential components for the design of these types of interventions, and how contextual factors may influence program implementation. Variability in program design is important to consider as it may influence anticipated effects, a next step for the research team. Results may also inform stakeholders should they wish to implement similar programs to increase access to specialized health services via primary care.


2020 ◽  
Vol 16 (12) ◽  
pp. e1008492
Author(s):  
Abhishek Mallela ◽  
Maulik K. Nariya ◽  
Eric J. Deeds

Protein turnover is vital to cellular homeostasis. Many proteins are degraded efficiently only after they have been post-translationally “tagged” with a polyubiquitin chain. Ubiquitylation is a form of Post-Translational Modification (PTM): addition of a ubiquitin to the chain is catalyzed by E3 ligases, and removal of ubiquitin is catalyzed by a De-UBiquitylating enzyme (DUB). Nearly four decades ago, Goldbeter and Koshland discovered that reversible PTM cycles function like on-off switches when the substrates are at saturating concentrations. Although this finding has had profound implications for the understanding of switch-like behavior in biochemical networks, the general behavior of PTM cycles subject to synthesis and degradation has not been studied. Using a mathematical modeling approach, we found that simply introducing protein turnover to a standard modification cycle has profound effects, including significantly reducing the switch-like nature of the response. Our findings suggest that many classic results on PTM cycles may not hold in vivo where protein turnover is ubiquitous. We also found that proteins sharing an E3 ligase can have closely related changes in their expression levels. These results imply that it may be difficult to interpret experimental results obtained from either overexpressing or knocking down protein levels, since changes in protein expression can be coupled via E3 ligase crosstalk. Understanding crosstalk and competition for E3 ligases will be key in ultimately developing a global picture of protein homeostasis.


2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Udayan Bhattacharya ◽  
Fiifi Neizer-Ashun ◽  
Priyabrata Mukherjee ◽  
Resham Bhattacharya

AbstractDeubiquitination is now understood to be as important as its partner ubiquitination for the maintenance of protein half-life, activity, and localization under both normal and pathological conditions. The enzymes that remove ubiquitin from target proteins are called deubiquitinases (DUBs) and they regulate a plethora of cellular processes. DUBs are essential enzymes that maintain intracellular protein homeostasis by recycling ubiquitin. Ubiquitination is a post-translational modification where ubiquitin molecules are added to proteins thus influencing activation, localization, and complex formation. Ubiquitin also acts as a tag for protein degradation, especially by proteasomal or lysosomal degradation systems. With ~100 members, DUBs are a large enzyme family; the ubiquitin-specific peptidases (USPs) being the largest group. USP10, an important member of this family, has enormous significance in diverse cellular processes and many human diseases. In this review, we discuss recent studies that define the roles of USP10 in maintaining cellular function, its involvement in human pathologies, and the molecular mechanisms underlying its association with cancer and neurodegenerative diseases. We also discuss efforts to modulate USPs as therapy in these diseases.


2004 ◽  
Vol 71 ◽  
pp. 107-120 ◽  
Author(s):  
Sruti Shiva ◽  
Doug Moellering ◽  
Anup Ramachandran ◽  
Anna-Liisa Levonen ◽  
Aimee Landar ◽  
...  

Cellular redox signalling is mediated by the post-translational modification of proteins in signal-transduction pathways by ROS/RNS (reactive oxygen species/reactive nitrogen species) or the products derived from their reactions. NO is perhaps the best understood in this regard with two important modifications of proteins known to induce conformational changes leading to modulation of function. The first is the addition of NO to haem groups as shown for soluble guanylate cyclase and the newly discovered NO/cytochrome c oxidase signalling pathway in mitochondria. The second mechanism is through the modification of thiols by NO to form an S-nitrosated species. Other ROS/RNS can also modify signalling proteins although the mechanisms are not as clearly defined. For example, electrophilic lipids, formed as the reaction products of oxidation reactions, orchestrate adaptive responses in the vasculature by reacting with nucleophilic cysteine residues. In modifying signalling proteins ROS/RNS appear to change the overall activity of signalling pathways in a process that we have termed 'redox tone'. In this review, we discuss these different mechanisms of redox cell signalling, and give specific examples of ROS/RNS participation in signal transduction.


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