scholarly journals Molecular basis for specificity of the Met1-linked polyubiquitin signal

2016 ◽  
Vol 44 (6) ◽  
pp. 1581-1602 ◽  
Author(s):  
Paul R. Elliott
Keyword(s):  
Molecular Mechanisms ◽  
Cellular Responses ◽  
Signalling Pathways ◽  
Post Translational Modification ◽  
Polyubiquitin Chains ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Ubiquitin Binding ◽  
Inflammatory Signalling ◽  
Unique Ability

The post-translational modification of proteins provides a rapid and versatile system for regulating all signalling pathways. Protein ubiquitination is one such type of post-translational modification involved in controlling numerous cellular processes. The unique ability of ubiquitin to form polyubiquitin chains creates a highly complex code responsible for different subsequent signalling outcomes. Specialised enzymes (‘writers’) generate the ubiquitin code, whereas other enzymes (‘erasers’) disassemble it. Importantly, the ubiquitin code is deciphered by different ubiquitin-binding proteins (‘readers’) functioning to elicit particular cellular responses. Ten years ago, the methionine1 (Met1)-linked (linear) polyubiquitin code was first identified and the intervening years have witnessed a seismic shift in our understanding of Met1-linked polyubiquitin in cellular processes, particularly inflammatory signalling. This review will discuss the molecular mechanisms of specificity determination within Met1-linked polyubiquitin signalling.

scholarly journals SUMOylation pathway alteration coupled with downregulation of SUMO E2 enzyme at mucosal epithelium modulates inflammation in inflammatory bowel disease

Open Biology ◽  
2017 ◽  
Vol 7 (6) ◽  
pp. 170024 ◽  
Author(s):  
Salman Ahmad Mustfa ◽  
Mukesh Singh ◽  
Aamir Suhail ◽  
Gayatree Mohapatra ◽  
Smriti Verma ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Endoscopic Biopsy ◽  
Spectrometric Analysis ◽  
Post Translational Modification ◽  
Inflammatory Gene Expression ◽  
Cellular Processes ◽  
Mucosal Tissues ◽  
Inflammatory Bowel ◽  
Inflammatory Signalling

Post-translational modification pathways such as SUMOylation are integral to all cellular processes and tissue homeostasis. We investigated the possible involvement of SUMOylation in the epithelial signalling in Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD). Initially in a murine model of IBD, induced by dextran–sulfate–sodium (DSS mice), we observed inflammation accompanied by a lowering of global SUMOylation of colonic epithelium. The observed SUMOylation alteration was due to a decrease in the sole SUMO E2 enzyme (Ubc9). Mass-spectrometric analysis revealed the existence of a distinct SUMOylome (SUMO-conjugated proteome) in DSS mice with alteration of key cellular regulators, including master kinase Akt1. Knocking-down of Ubc9 in epithelial cells resulted in dramatic activation of inflammatory gene expression, a phenomenon that acted via reduction in Akt1 and its SUMOylated form. Importantly, a strong decrease in Ubc9 and Akt1 was also seen in endoscopic biopsy samples ( N = 66) of human CD and UC patients. Furthermore, patients with maximum disease indices were always accompanied by severely lowered Ubc9 or SUMOylated-Akt1. Mucosal tissues with severely compromised Ubc9 function displayed higher levels of pro-inflammatory cytokines and compromised wound-healing markers. Thus, our results reveal an important and previously undescribed role for the SUMOylation pathway involving Ubc9 and Akt1 in modulation of epithelial inflammatory signalling in IBD.

scholarly journals Robust high-throughput assays to assess discrete steps in ubiquitination and related cascades

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Gabriel Fenteany ◽  
Paras Gaur ◽  
Gaurav Sharma ◽  
Lajos Pintér ◽  
Ernő Kiss ◽  
...  
Keyword(s):  
High Throughput ◽  
Basic Research ◽  
Nuclear Antigen ◽  
Therapeutic Drug ◽  
Post Translational Modification ◽  
Good Correspondence ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Ubiquitin Conjugating Enzyme ◽  
Covalent Adducts

Abstract Background Ubiquitination and ubiquitin-like protein post-translational modifications play an enormous number of roles in cellular processes. These modifications are constituted of multistep reaction cascades. Readily implementable and robust methods to evaluate each step of the overall process, while presently limited, are critical to the understanding and modulation of the reaction sequence at any desired level, both in terms of basic research and potential therapeutic drug discovery and development. Results We developed multiple robust and reliable high-throughput assays to interrogate each of the sequential discrete steps in the reaction cascade leading to protein ubiquitination. As models for the E1 ubiquitin-activating enzyme, the E2 ubiquitin-conjugating enzyme, the E3 ubiquitin ligase, and their ultimate substrate of ubiquitination in a cascade, we examined Uba1, Rad6, Rad18, and proliferating cell nuclear antigen (PCNA), respectively, in reconstituted systems. Identification of inhibitors of this pathway holds promise in cancer therapy since PCNA ubiquitination plays a central role in DNA damage tolerance and resulting mutagenesis. The luminescence-based assays we developed allow for the quantitative determination of the degree of formation of ubiquitin thioester conjugate intermediates with both E1 and E2 proteins, autoubiquitination of the E3 protein involved, and ubiquitination of the final substrate. Thus, all covalent adducts along the cascade can be individually probed. We tested previously identified inhibitors of this ubiquitination cascade, finding generally good correspondence between compound potency trends determined by more traditional low-throughput methods and the present high-throughput ones. Conclusions These approaches are readily adaptable to other E1, E2, and E3 systems, and their substrates in both ubiquitination and ubiquitin-like post-translational modification cascades.

scholarly journals When the chains do not break: the role of USP10 in physiology and pathology

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Udayan Bhattacharya ◽  
Fiifi Neizer-Ashun ◽  
Priyabrata Mukherjee ◽  
Resham Bhattacharya
Keyword(s):  
Complex Formation ◽  
Molecular Mechanisms ◽  
Protein Homeostasis ◽  
Post Translational Modification ◽  
Intracellular Protein ◽  
Lysosomal Degradation ◽  
Life Activity ◽  
Cellular Processes ◽  
Pathological Conditions

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.

scholarly journals Post-translational regulation of ubiquitin signaling

2019 ◽  
Vol 218 (6) ◽  
pp. 1776-1786 ◽  
Author(s):  
Lei Song ◽  
Zhao-Qing Luo
Keyword(s):  
Translational Regulation ◽  
Covalent Attachment ◽  
Immune Disorders ◽  
Post Translational Modification ◽  
Polyubiquitin Chains ◽  
Cellular Processes ◽  
Lysine Residues ◽  
Substrate Proteins ◽  
Ubiquitination Machinery ◽  
Integrate Development

Ubiquitination regulates many essential cellular processes in eukaryotes. This post-translational modification (PTM) is typically achieved by E1, E2, and E3 enzymes that sequentially catalyze activation, conjugation, and ligation reactions, respectively, leading to covalent attachment of ubiquitin, usually to lysine residues of substrate proteins. Ubiquitin can also be successively linked to one of the seven lysine residues on ubiquitin to form distinctive forms of polyubiquitin chains, which, depending upon the lysine used and the length of the chains, dictate the fate of substrate proteins. Recent discoveries revealed that this ubiquitin code is further expanded by PTMs such as phosphorylation, acetylation, deamidation, and ADP-ribosylation, on ubiquitin, components of the ubiquitination machinery, or both. These PTMs provide additional regulatory nodes to integrate development or insulting signals with cellular homeostasis. Understanding the precise roles of these PTMs in the regulation of ubiquitin signaling will provide new insights into the mechanisms and treatment of various human diseases linked to ubiquitination, including neurodegenerative diseases, cancer, infection, and immune disorders.

scholarly journals Protein SUMOylation modification and its associations with disease

Open Biology ◽  
2017 ◽  
Vol 7 (10) ◽  
pp. 170167 ◽  
Author(s):  
Yanfang Yang ◽  
Yu He ◽  
Xixi Wang ◽  
Ziwei liang ◽  
Gu He ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Growth ◽  
High Throughput ◽  
Molecular Mechanisms ◽  
Cellular Responses ◽  
Biological Functions ◽  
Post Translational Modification ◽  
Sumoylation Site ◽  
Signal Crosstalk ◽  
Protein Sumoylation

SUMOylation, as a post-translational modification, plays essential roles in various biological functions including cell growth, migration, cellular responses to stress and tumorigenesis. The imbalance of SUMOylation and deSUMOylation has been associated with the occurrence and progression of various diseases. Herein, we summarize and discuss the signal crosstalk between SUMOylation and ubiquitination of proteins, protein SUMOylation relations with several diseases, and the identification approaches for SUMOylation site. With the continuous development of bioinformatics and mass spectrometry, several accurate and high-throughput methods have been implemented to explore small ubiquitin-like modifier-modified substrates and sites, which is helpful for deciphering protein SUMOylation-mediated molecular mechanisms of disease.

scholarly journals Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

2021 ◽  
Vol 14 (9) ◽  
pp. 848
Author(s):  
Lucas Cruz ◽  
Paula Soares ◽  
Marcelo Correia
Keyword(s):  
Protein Function ◽  
Deubiquitinating Enzymes ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Cellular Targets ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Damage Repair ◽  
Ubiquitin Molecule

Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.

Recent development of machine learning methods in sumoylation sites prediction

2021 ◽  
Vol 28 ◽  
Author(s):  
Yi-Wei Zhao ◽  
Shihua Zhang ◽  
Hui Ding
Keyword(s):  
Machine Learning ◽  
Molecular Mechanisms ◽  
Prediction Models ◽  
Computational Prediction ◽  
Research Progress ◽  
Post Translational Modification ◽  
Sumoylation Site ◽  
Cellular Processes ◽  
Online Tools ◽  
Experimental Approaches

: Sumoylation of proteins is an important reversible post-translational modification of proteins and mediates a variety of cellular processes. Sumo-modified proteins can change their subcellular localization, activity and stability. In addition, it also plays an important role in various cellular processes such as transcriptional regulation and signal transduction. The abnormal sumoylation is involved in many diseases, including neurodegeneration and immune-related diseases, as well as the development of cancer. Therefore, identification of the sumoylation site (SUMO site) is fundamental to understanding their molecular mechanisms and regulatory roles. In contrast to labor-intensive and costly experimental approaches, computational prediction of sumoylation sites in silico also attracted much attention for its accuracy, convenience and speed. At present, many computational prediction models have been used to identify SUMO sites, but these contents have not been comprehensively summarized and reviewed. Therefore, the research progress of relevant models is summarized and discussed in this paper. We will briefly summarize the development of bioinformatics methods on sumoylation site prediction. We will mainly focus on the benchmark dataset construction, feature extraction, machine learning method, published results and online tools. We hope the review will provide more help for wet-experimental scholars.

A methodology for carbamate post-translational modification discovery and its application in Escherichia coli

2021 ◽  
Vol 11 (2) ◽  
pp. 20200028
Author(s):  
Victoria L. Linthwaite ◽  
Martin J. Cann
Keyword(s):  
Escherichia Coli ◽  
Carbon Dioxide ◽  
Arabidopsis Thaliana ◽  
Protein Interactions ◽  
Signalling Pathways ◽  
Post Translational Modification ◽  
Cellular Targets ◽  
Biologically Relevant ◽  
Cellular Processes ◽  
Cell Phenotypes

Carbon dioxide can influence cell phenotypes through the modulation of signalling pathways. CO 2 regulates cellular processes as diverse as metabolism, cellular homeostasis, chemosensing and pathogenesis. This diversity of regulated processes suggests a broadly conserved mechanism for CO 2 interactions with diverse cellular targets. CO 2 is generally unreactive but can interact with neutral amines on protein under normal intracellular conditions to form a carbamate post-translational modification (PTM). We have previously demonstrated the presence of this PTM in a subset of protein produced by the model plant species Arabidopsis thaliana . Here, we describe a detailed methodology for identifying new carbamate PTMs in an extracted soluble proteome under biologically relevant conditions. We apply this methodology to the soluble proteome of the model prokaryote Escherichia coli and identify new carbamate PTMs . The application of this methodology, therefore, supports the hypothesis that the carbamate PTM is both more widespread in biology than previously suspected and may represent a broadly relevant mechanism for CO 2 –protein interactions.

scholarly journals Ubiquitomics: An Overview and Future

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1453 ◽  
Author(s):  
George Vere ◽  
Rachel Kealy ◽  
Benedikt M. Kessler ◽  
Adan Pinto-Fernandez
Keyword(s):  
Chemical Biology ◽  
Biological Diversity ◽  
Analytical Techniques ◽  
Cellular Proteins ◽  
Covalent Attachment ◽  
Post Translational Modification ◽  
Polyubiquitin Chains ◽  
Protein Substrates ◽  
Protein Ubiquitination ◽  
Amino Acid Side Chains

Covalent attachment of ubiquitin, a small globular polypeptide, to protein substrates is a key post-translational modification that determines the fate, function, and turnover of most cellular proteins. Ubiquitin modification exists as mono- or polyubiquitin chains involving multiple ways how ubiquitin C-termini are connected to lysine, perhaps other amino acid side chains, and N-termini of proteins, often including branching of the ubiquitin chains. Understanding this enormous complexity in protein ubiquitination, the so-called ‘ubiquitin code’, in combination with the ∼1000 enzymes involved in controlling ubiquitin recognition, conjugation, and deconjugation, calls for novel developments in analytical techniques. Here, we review different headways in the field mainly driven by mass spectrometry and chemical biology, referred to as “ubiquitomics”, aiming to understand this system’s biological diversity.

scholarly journals The structure and function of deubiquitinases: lessons from budding yeast

Open Biology ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 200279
Author(s):  
Harsha Garadi Suresh ◽  
Natasha Pascoe ◽  
Brenda Andrews
Keyword(s):  
Protein Quality ◽  
Budding Yeast ◽  
Post Translational Modification ◽  
Repair Gene ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Damage Repair ◽  
The Many ◽  
Key Aspects ◽  
And Function

Protein ubiquitination is a key post-translational modification that regulates diverse cellular processes in eukaryotic cells. The specificity of ubiquitin (Ub) signalling for different bioprocesses and pathways is dictated by the large variety of mono-ubiquitination and polyubiquitination events, including many possible chain architectures. Deubiquitinases (DUBs) reverse or edit Ub signals with high sophistication and specificity, forming an integral arm of the Ub signalling machinery, thus impinging on fundamental cellular processes including DNA damage repair, gene expression, protein quality control and organellar integrity. In this review, we discuss the many layers of DUB function and regulation, with a focus on insights gained from budding yeast. Our review provides a framework to understand key aspects of DUB biology.

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