SUMOylation and Ubiquitination: Current and Emerging Concepts
"a comprehensive, in-depth resource ... intensive and technically detailed descriptions of the latest advances ... densely packed with information ... a valuable reference for any laboratory group working in this field" (Doodys)
Caister Academic Press
Van G. Wilson
Texas A&M College of Medicine, USA
viii + 504
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Most proteins undergo post-translational modifications altering physical and chemical properties, folding, conformation distribution, stability, activity and function. Ubiquitin and SUMOs are related small proteins that are members of the large ubiquitin superfamily of post-translational modifiers.
Written by highly respected leaders in their fields under the expert guidance of the editor, this volume covers the principles of ubiquitination and SUMOylation, presents detailed reviews of current and emerging concepts and highlights new advances in all areas of SUMOylation and ubiquitination. Topics of note include: the ubiquitin superfamily, the ubiquitin toolbox, onco viral exploitation of the SUMO system, small molecule modulators of desumoylation, mass spectrometry, global proteomic profiling of SUMO and ubiquitin, biotin-based approaches, genetic screening, SUMOylation networks in humans, targets for ubiquitin ligases, regulation of p53, protein homeostasis, miRNAs, DNA replication, DNA damage response, telomere biology, intracellular trafficking, regulation of angiogenesis, brain ischemia, autophagy, assembly and activity, antiviral defense, HIV infection, amyloid and amyloid-like proteins, plant immunity.
This comprehensive and up-to-date book is the definitive reference volume on all aspects of SUMOylation and ubiquitination and is an essential acquisition for anyone involved in this area of biology.
"This is a comprehensive and in-depth overview of recent advances in our understanding of the physiological roles and mechanisms of action of these important regulatory covalent modifications. In addition, the book offers a technically rich description of the latest advances in the use of proteomic techniques to study the modification process and identify novel targets ... This is a comprehensive, in-depth resource for persons interested in the processes of ubiquitination and SUMOylation ... the book is at its best as a source of intensive and technically detailed descriptions of the latest advances in knowledge and methodology for active practitioners, whether graduate students, research associates, or principle investigators, both in their specific area of investigation as well as the progress across the field as a whole. The breadth and depth of coverage provided by an impressive group of experts renders this a valuable reference for any laboratory group working in this field ... The book is densely packed with information ... This book represents a novel and quality addition to this genre." from Doodys
Table of contents
1. The Rise of the Ubiquitin Super Family
Van G. Wilson
Ubiquitin and SUMOs are related small proteins that are members of the larger ubiquitin superfamily. Members of this family (Ubls) are post-translational modifiers that are covalently attached to target proteins through lysine residues in the target. Biochemically, the processing and conjugation of these modifiers is remarkably similar, although the individual enzymes and components are usually specific for their individual modifier. The modification process is dynamic with exact demodification occurring through specific proteases that remove the Ubls and restore the target proteins to their original state. Functionally, Ubl modification can influence many aspects of protein biology including activity, localization, stability, and interactions with partners. Importantly, examples of functional cross-talk between Ub and SUMO modifications have been observed, which provides exciting opportunities for combinatorial regulation of target proteins. This chapter will introduce basic principles of ubiquitinylation and sumoylation and will also provide a general overview of important terms and concepts that will be explored in more detail in the remaining chapters.
2. Cracking the Ubiquitin Code: the Ubiquitin Toolbox Free download
Monique P.C. Mulder, Katharina F. Witting and Huib Ovaa
Ubiquitination, a post-translational modification, regulates a vast array of fundamental biological processes with dysregulation of the dedicated enzymes giving rise to pathologies such as cancer and neurodegenerative diseases. Assembly and its ensuing removal of this post-translational modification, determining a large variety of biological functions, is executed by a number of enzymes sequentially activating, conjugating, ligating, as well deubiquitinating. Considering the vast impact of ubiquitination on regulating cellular homeostasis, understanding the function of these vast enzyme networks merits the development and innovation of tools. Thus, advances in synthetic strategies for generating ubiquitin, permitted the development of a plethora of ubiquitin assay reagents and numerous activity-based probes (ABPs) enable the study of enzymes involved in the complex system of ubiquitination. With ubiquitination playing such a pivotal role in the pathogenesis of a multitude of diseases, the identification of inhibitors for ubiquitin enzymes as well as the development of ABPs and high-throughput assay reagents is of utmost importance. Accordingly, this chapter will review the current state-of-the-art activity-based probes, reporter substrates, and other relevant tools based on Ub as a recognition element while highlighting the need of innovative technologies and unique concepts to study emerging facets of ubiquitin biology.
3. Recent Highlights: Onco Viral Exploitation of the SUMO System Free download
Domenico Mattoscio, Alessandro Medda and Susanna Chiocca
Small ubiquitin-like modifier (SUMO)ylation is a crucial post-translational modification that controls functions of a wide collection of proteins and biological processes. Hence, given its pleiotropic role, viruses have developed many approaches to usurp SUMO conjugation to exploit the cellular host environment for their own benefit. Consistently, cancer cells also frequently impact on SUMO to force cellular transformation, underlying the importance of SUMO in health and diseases. Therefore, after a brief introduction to the multistep SUMOylation pathway, in this chapter we will focus our attention on several examples of strategies adopted by oncogenic viruses to hijack SUMOylation in order to promote infection, persistence and malignant transformation of host cells.
4. Progress in the Discovery of Small Molecule Modulators of DeSUMOylation Free download
Shiyao Chen, Duoling Dong, Weixiang Xin and Huchen Zhou
SUMOylation and DeSUMOylation are reversible protein post-translational modification (PTM) processes involving small ubiquitin-like modifier (SUMO) proteins. These processes have indispensable roles in various cellular processes, such as subcellular localization, gene transcription, and DNA replication and repair. Over the past decade, increasing attention has been given to SUMO-related pathways as potential therapeutic targets. The Sentrin/SUMO-specific protease (SENP), which is responsible for deSUMOylation, has been proposed as a potential therapeutic target in the treatment of cancers and cardiac disorders. Unfortunately, no SENP inhibitor has yet reached clinical trials. In this review, we focus on advances in the development of SENP inhibitors in the past decade.
5. Identification of SUMOylated and Ubiquitylated Substrates by Mass Spectrometry
Francis P. McManus and Pierre Thibault
Further understanding of the cross-talk taking place between protein SUMOylation and ubiquitylation can provide valuable insights into the biological function and turnover of proteins. Recent advances in sample preparation and the development of sensitive mass spectrometers enabled a systems-level view of this cross communication. Here, we highlight the evolution as well as the merits and limitations of the various workflows that have been created to monitor protein SUMOylation and ubiquitylation. Furthermore, this chapter delves into mass spectrometry centered approaches to study the co-occurrence of SUMOylation and ubiquitylation on proteins in a non-biased large-scale fashion using immunoaffinity enrichment that target either the co-modified proteins from cell extracts or the modified peptides of the corresponding proteins. Lastly, we provide a perspective on methods that will permit the global analysis of endogenous proteins modified by different ubiquitin-like proteins (UBLs).
6. Global Proteomic Profiling of SUMO and Ubiquitin
Alla Ahmad, Ryan Lumpkin and Elizabeth A. Komives
In this chapter, we introduce the small ubiquitin-like modifier (SUMO) and describe how it is attached to target proteins. What is known about how SUMO attachment changes the function of a target protein is briefly reviewed. The main focus of the chapter is to introduce the various methods for identifying SUMO attachment sites on target proteins using proteomics and mass spectrometry. Finally, we present a future outlook for one newly discovered function of SUMO that will be quite interesting to study using the new proteomics approaches.
7. Biotin-based Approaches for the Study of Ubiquitin and Ubiquitin-like Protein Modifications
James D. Sutherland, Orhi Barroso-Gomila and Rosa Barrio
Since its discovery, the high-affinity interaction between biotin and avidin has formed the basis of numerous tools and techniques in molecular biology and biochemistry. The post-translational modifications of cellular proteins via conjugation of ubiquitin (Ub) and ubiquitin-like (UbL) proteins contribute to crucial cellular processes, such as protein homeostasis and the DNA damage response, yet they are challenging to study due to their dynamic nature, scarcity, and sensitivity to removal by proteases. Understanding how the Ub/UbL-modified proteome changes during development or in response to environmental insults or pathological conditions may yield new biomarkers or identify new drug targets. The use of biotin-based technologies for Ub/UbL studies is relatively new but has already contributed to the identification of new substrates and promises much more. In this review, we focus on two separate approaches: biotin-tagged Ub/UbLs to modify and capture target proteins in vivo, and BioID, a tool to facilitate the labeling and identification of proximal interactors of Ub/UbL enzymes. Coupled with ongoing advances in proteomics to increase sensitivity in peptide identification, and gene-editing techniques to avoid overexpression artifacts, biotin-based systems promise to reveal new information about the role of Ub/UbL modifications in development and disease.
8. A Genetic Screening Method for Mammalian SUMOylated Proteins Using Split Fluorescence Protein Reconstitution
Maki Komiyaa, Mizuki Endoa and Takeaki Ozawaa
SUMOylation is an essential post-translational protein modification in various cellular functions. To clarify the role of SUMOylation, numerous screening approaches have been reported for the discovery of novel SUMOylated proteins. However, the reversibility of SUMOylation and the highly varied SUMOylation levels among targets have made it difficult to detect infrequently-SUMOylated proteins, especially in mammalian cells. Here, we describe a newly-developed screening system for mammalian SUMOylated proteins in living cells, which is based on split fluorescence protein reconstitution and fluorescence-based cell sorting technique. The experiments demonstrated that SUMOylation by SUMO2 was detectable as a fluorescence signal in living mammalian cells, which enabled exploration of SUMOylation candidates without cell destructive processes. The system successfully identified 36 unreported SUMO2-substrate candidates, of which Atac2 was shown as SUMOylated at a lysine 408. We summarized the applicability to other SUMO isoforms and various cell types, which will be able to contribute to broader exploration of the roles of SUMOylation in numerous biological phenomena.
9. Dissecting Complex SUMOylation Networks in Humans
Ijeoma Uzoma and Heng Zhu
To continue improving our understanding of the physiological impact of SUMO modification in humans at a global level, dissecting enzyme/SUMO/substrate relationships within the complex SUMOylation network is essential. This effort requires multifaceted proteomic approaches that can capture comprehensive data on SUMO substrates, E3 ligase-substrate specificity, SUMO paralogue specificity, and SUMO-binding proteins. The Hu Prot™ protein microarray contains > 20,000 purified human proteins, providing an ideal platform for identification of substrates that can be covalently modified by SUMO-1 or -2, as well as proteins that recognize SUMO substrates through non-covalent interactions. Protein microarray studies successfully identified > 2500 covalent SUMO substrates, linked several E3 ligases to hundreds of their protein substrates, established SUMO paralogue preference for substrates and E3 ligases, and identified hundreds of SUMO-binding proteins. These large-scale protein microarray datasets were integrated to construct a multidimensional SUMO network that can be used to connect substrates to upstream E3 ligases and to predict SUMO-dependent protein-protein interactions. By enhancing our knowledge of the architecture and regulation of the enzyme-substrate network, we can strengthen our understanding of the functional outcomes of SUMO modification in human cells.
10. TULIP: Targets of Ubiquitin Ligases Identified by Proteomics
Román González-Prieto and Alfred C.O. Vertegaal
Ubiquitin is a small protein that can be attached to thousands of substrates via an enzymatic cascade involving an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3). Over 600 different human E3 ligases have been found. The identification of specific targets for ubiquitin E3 ligases is challenging. So far, most of the approaches aimed to identify E3-specific substrates rely on indirect evidence. Here, we would like to introduce TULIP (Targets of Ubiquitin Ligases Identified by Proteomics) methodology, which enables the identification of ubiquitin E3-specific targets in a direct manner. The rationale behind this strategy is that on construction of a linear fusion between an E3 of interest and ubiquitin, this ubiquitin moiety will be employed by the linked E3 to modify its substrates. Subsequently, trapped substrates are purified in denaturing buffers to remove non-covalent interactors. Starting from the cDNA sequence of an E3 ligase of interest and finishing with the identification of the ubiquitination targets by mass spectrometry-based proteomics, the whole process takes between 4 to 6 weeks. The description of the methodology includes a discussion of potential pitfalls and specific recommendations.
11. Regulation of P53 Family Members by the Ubiquitin and SUMO Modification Systems
Viola Calabrò and Maria Vivo
The p53 family includes, in addition to the well-known tumour suppressor p53, two additional proteins, p63 and p73. These proteins are encoded by two different genes, each of them subjected to different activation modes. All family members have an essential role in either tumourigenesis or morphogenesis. The high degree of identity among the three protein sequences is mirrored by the existence of a common modular protein structure. All of them present a transactivation (TA), a DNA-binding (DBD) and an oligomerization (OD) domain, with a high level of sequence identity. Each gene gives rise to multiple isoforms because of differential promoter selection and alternative splicing at both 5′ and 3′ ends of the mRNA. Despite the homology, p53, p63 or p73 gene inactivation in mice gave rise to different phenotypes indicating that the proteins encoded by these genes play different roles. While p53 has the central function of tumour suppressor, both p63 and p73 are actively involved in development and differentiation. A complex set of post-translational modifications such as phosphorylation, acetylation, ribosylation, glycosylation, ubiquitylation and SUMOylation, with often-intertwined modes of action regulates p53 family members functions. Ubiquitylation and SUMOylation appear to affect transactivation ability, localization and stabilization of these transcriptional factors and to confer their timely regulated role during differentiation and development. In this chapter, the role of p53 family members will be described as well as the impact of ubiquitylation and SUMOylation on their functions. Moreover, other ubiquitin-like proteins have also been shown to regulate p53 family members activity. The interaction of the Ub/SUMO system with the complex regulation pathways of both tumour suppression and development guaranteed by the p53 family members constitutes an example of critical control machinery regulating cellular fate.
12. Interplay of the Ubiquitin Proteasome System and Mitochondria in Protein Homeostasis Free download
Mafalda Escobar-Henriques, Selver Altin and Fabian den Brave
Eukaryotic cells are subdivided into membrane-bound compartments specialised in different cellular functions and requiring dedicated sets of proteins. Mitochondria are essential organelles whose proper functioning is critical for cellular health. Although cells developed compartment-specific mechanisms for protein quality control, chaperones and ubiquitin are generally required for maintaining cellular proteostasis. Proteotoxic stress is signalled from one compartment into another to adjust the cellular stress response. Moreover, transport of misfolded proteins between different compartments can buffer local defects in protein quality control. Mitochondria are special organelles in that they possess an own expression, folding and proteolytic machinery, of bacterial origin, which do not have ubiquitin. Nevertheless, the importance of extensive crosstalk between mitochondria and other subcellular compartments is increasingly clear. Here, we will present local quality control mechanisms and discuss how cellular proteostasis is affected by the interplay between mitochondria and the ubiquitin proteasome system.
13. Interplay of Ubiquitination and SUMOylation with miRNAs
Yashika Agrawal and Manas Kumar Santra
A myriad of processes occurring in each individual cell govern the functions of tissues and the overall activity of multicellular organisms. Stringent and precise multilevel control of these cellular pathway components dictates the normal functioning of cells. This control, to maintain the homeostasis in the cells, is exercised at various levels including transcription, post-transcription, translation and post-translation. miRNAs have emerged as major players regulating the post-transcriptional events in the cells, whereas ubiquitination and sumoylation are among the major post-translational events. The following sections in this chapter will discuss miRNAs, namely their synthesis and functions, the processes of ubiquitination and sumoylation and how these different level modifications crosstalk with each other in order to regulate the normal and diseased states of individuals.
14. The Role of Ubiquitylation and SUMOylation in DNA Replication Free download
DNA replication is a tightly regulated conserved process that ensures the faithful transmission of genetic material to define heritable phenotypic traits. Perturbations in this process result in genomic instability, mutagenesis, and diseases, including malignancy. Proteins involved in the initiation, progression, and termination of DNA replication are subject to a plethora of reversible post-translational modifications (PTMs) to provide a proper temporal and spatial control of replication. Among these, modifications involving the covalent attachment of the small protein ubiquitin or the small ubiquitin-like modifier (SUMO) to replication and replication-associated proteins are particularly important for the proper regulation of DNA replication as well as for optimal cellular responses to replication stress. In this chapter, we describe how the ubiquitylation and SUMOylation processes impact DNA replication in eukaryotes and highlight the consequence of deregulated signals emanating from these two versatile regulatory pathways on cellular activities.
15. Roles of Ubiquitination and SUMOylation in DNA Damage Response Free download
Siyuan Su, Yanqiong Zhang and Pengda Liu
Ubiquitin and ubiquitin-like modifiers, such as SUMO, exert distinct physiological functions by conjugating to protein substrates. Ubiquitination or SUMOylation of protein substrates determine the fate of modified proteins, including proteasomal degradation, cellular re-localisation, alternations in binding partners and serving as a protein-binding platform, in a ubiquitin or SUMO linkage-dependent manner. DNA damage occurs constantly in living organisms but is also repaired by distinct tightly controlled mechanisms including homologous recombination, non-homologous end joining, inter-strand crosslink repair, nucleotide excision repair and base excision repair. Upon sensing damaged DNA, a ubiquitination/SUMOylation landscape is established to recruit DNA damage repair factors. Meanwhile, misloaded and mission-completed repair factors will be turned over by ubiquitin or SUMO modifications as well. These ubiquitination and SUMOylation events are tightly controlled by both E3 ubiquitin/SUMO ligases and deubiquitinases/deSUMOylases. In this chapter, we will summarize identified ubiquitin and SUMO-related modifications and their function in distinct DNA damage repair pathways, and provide evidence for responsible E3 ligases, deubiquitinases, SUMOylases and deSUMOylases in these processes. Given that genome instability leads to human disorders including cancer, understanding detailed molecular mechanisms for ubiquitin and SUMO-related regulations in DNA damage response may provide novel insights into therapeutic modalities to treat DNA-damage-related human diseases.
16. The Role of Ubiquitination and SUMOylation in Telomere Biology Free download
Michal Zalzman, W. Alex Meltzer, Benjamin A. Portney, Robert A. Brown and Aditi Gupta
Telomeres are a unique structure of DNA repeats covered by proteins at the ends of the chromosomes that protect the coding regions of the genome and function as a biological clock. They require a tight regulation of the factors covering and protecting their structure, as they are shortened with each cell division to limit the ability of cells to replicate uncontrollably. Additionally, they protect the chromosome ends from DNA damage responses and thereby, prevent genomic instability. Telomere dysfunction can lead to chromosomal abnormalities and cancer. Therefore, dysregulation of any of the factors that regulate the integrity of the telomeres will have implications to chromosomal stability, replicative lifespan and may lead to cell transformation. This chapter will cover the main factors participating in the normal function of the telomeres and how these are regulated by the ubiquitin and SUMO systems. Accumulating evidence indicate that the ubiquitin and SUMO pathways are significant regulators of the shelterin complex and other chromatin modifiers, which are important for telomere structure integrity. Furthermore, the crosstalk between these two pathways has been reported in telomeric DNA repair. A better understanding of the factors contributing to telomere biology, and how they are regulated, is important for the design of new strategies for cancer therapies and regenerative medicine.
17. Role of Ubiquitin and SUMO in Intracellular Trafficking Free download
Precise location of proteins at a given time within a cell is essential to convey specific signals and result in a relevant functional outcome. Small ubiquitin-like modifications, such as ubiquitin and SUMO, represent a delicate and diverse way to transiently regulate intracellular trafficking events of existing proteins in cells. Trafficking of multiple proteins is controlled reversibly by ubiquitin and/or SUMO directly or indirectly via regulation of transport machinery components. Regulation is dynamic and multilayered, involving active crosstalk and interdependence between post-translational modifications. However, in most cases regulation appears very complex and the mechanistic details regarding how ubiquitin and SUMO control protein location in cells are not yet well understood. Moreover, most of the findings still lack in vivo
evidence in multicellular organisms.
18. Roles of Ubiquitination and SUMOylation in the Regulation of Angiogenesis Free download
Andrea Rabellino, Cristina Andreani and Pier Paolo Scaglioni
The generation of new blood vessels from the existing vasculature is a dynamic and complex mechanism known as angiogenesis. Angiogenesis occurs during the entire lifespan of vertebrates and participates in many physiological processes. Furthermore, angiogenesis is also actively involved in many human diseases and disorders, including cancer, obesity and infections. Several inter-connected molecular pathways regulate angiogenesis, and post-translational modifications, such as phosphorylation, ubiquitination and SUMOylation, tightly regulate these mechanisms and play a key role in the control of the process. Here, we describe in detail the roles of ubiquitination and SUMOylation in the regulation of angiogenesis.
19. The Role of SUMOylation and Ubiquitination in Brain Ischaemia: Critical Concepts and Clinical Implications Free download
Joshua D. Bernstock, Daniel G. Ye, Dagoberto Estevez, Gustavo Chagoya, Ya-Chao Wang, Florian Gessler, John M. Hallenbeck and Wei Yang
Brain ischaemia is a severe form of metabolic stress that activates a cascade of pathological events involving many signalling pathways. Modulation of these pathways is largely mediated by post-translational modifications (PTMs). Indeed, PTMs can rapidly modify pre-existing proteins by attaching chemical or polypeptide moieties to selected amino acid residues, altering their functions, stability, subcellular localizations, or interactions with other proteins. Subsequently, related signalling pathways can be substantially affected. Thus, PTMs are widely deployed by cells as an adaptive strategy at the front line to efficiently cope with internal and external stresses. Many types of PTMs have been identified, including phosphorylation, O-GlcNAcylation, small ubiquitin-like modifier (SUMO) modification (SUMOylation), and ubiquitination. All these PTMs have been studied in brain ischaemia to some extent. In particular, a large body of evidence has demonstrated that both global SUMOylation and ubiquitination are massively activated after brain ischaemia, and this activation may play a critical role in defining the fate and function of cells in the post-ischaemic brain. The goal of this chapter will be to summarise the current findings on SUMOylation and ubiquitination in brain ischaemia and discuss their clinical implications.
20. The Role of Ubiquitylation and SUMOylation in Autophagy
Post-translational modifications such as ubiquitination and sumoylation are central players in determining the fates of proteins by providing specificity to mediate their degradation or alteration of functions. Ubiquitin is the central molecule in the ubiquitin-proteasome system (UPS), which works by tagging the proteins to be degraded with polyubiquitin chains, a mark identified by the barrel-shaped proteasome as an 'eat-me' signal. Autophagy, on the other hand, is a vesicular trafficking system specialized in degrading larger cargos and long-lived proteins in the lysosome. Until recently, autophagy and UPS were considered separate protein degradation machineries owing to their different molecular machineries and substrate preferences. However, elegant studies conducted in the last decade have demonstrated the interplay between autophagy and UPS at the molecular and functional levels. Among the most prominent molecule facilitating autophagy and UPS crosstalk is ubiquitin and recent studies have implicated the role of small Ub-like modifiers (SUMO) in autophagy as well. This chapter highlights the current understandings of the role of ubiquitin and SUMO in the regulation of autophagy.
21. Ubiquitin and SUMO Modifications in Caenorhabditis elegans
Stress Response Free download
Post-translation protein modifications by ubiquitin, SUMO and other ubiquitin-like modifiers is common and essential for all eukaryotic organisms. Ubiquitin, SUMO and other ubiquitin-like modifiers are attached to target proteins by a set of related but distinct enzymes including activating enzyme, conjugating enzyme, a ligase and in some cases auxiliary proteins. Both ubiquitin and SUMO proteins regulate most physiological processes in cells and often interdependence of the protein modifications can be observed. Discoveries of ubiquitin and SUMO function have been predominantly driven by studies in cell systems and by in vitro approaches. Investigations of post-translational modifications in Caenorhabditis elegans
promises new avenues in ubiquitin and SUMO research. It enables a whole organism approach to study post-translational modifications in development, stress, aging and in disease models. The biochemical mechanisms of ubiquitin and SUMO modifications are essentially conserved in C. elegans
and have been described elsewhere. Thus, this review focuses on emerging research areas where research in C. elegans
is advantageous and strongly advances the field of post-translational modifications by ubiquitin and SUMO.
22. Beyond Degradation: Ubiquitination of the Inflammasome Regulates Assembly and Activity
Joseph S. Bednash and Rama K. Mallampalli
First described in 2002, the inflammasome is a molecular platform that facilitates the maturation of the pro-inflammatory cytokines, interleukin (IL)-1b and IL-18. Now almost two decades since its discovery, understanding of inflammasome form and function has expanded greatly. Inflammasome-driven inflammation has been implicated in numerous human diseases including inflammatory arthritis, colitis, colorectal cancer, atherosclerosis, neurodegenerative disease, and metabolic disorders including non-alcoholic fatty liver disease and diabetes mellitus. As such, inflammasome regulation is of particular interest and relevance in the search for novel therapies. Numerous molecular processes have been implicated as key regulators of inflammasome function, and its regulation is multilayered, implicating the importance of this signaling pathway. Here, we focus on post-translational ubiquitin (Ub) modification as a key mechanism of inflammasome modulation. In regulating the inflammasomes, ubiquitin provides a molecular signature for inflammasome activity as well as functioning as a marker for protein degradation.
23. Ubiquitin and SUMO in Antiviral Defence
Van G. Wilson
The three branches of immunity, intrinsic, innate, and acquired, are each critical for antiviral defense. Intrinsic immunity consists of immediate, pre-existing mechanisms to limit replication and spread of invading viruses. Innate immunity produces a massive response to generate secreted interferons and cytokines that generate an antiviral state in recipient cells that can reduce viral reproduction through multiples mechanisms. Additionally, these secreted chemokines help prime the acquired immune response. The acquired immune response has two arms, the cellular and the humoral. Collectively these responses will finally clear infections and establish long-lasting protection through immune memory. Each of these complex systems needs careful regulation to ensure timely and faithful response to foreign pathogens and to ensure that the responses are down-regulated appropriately to prevent excessive host cell damage. Major regulators of immunity include ubiquitin and ubiquitin-like (Ubls) proteins, primarily the SUMO family. Ubiquitin and SUMOs are post-translationally attached to many immune system proteins to either activate or reduce target protein function. These modifications are in turn reversible via specific proteases (deubiquitinases or SUMO proteases known as SENPs) adding further dynamic regulation through varying the levels of modification and demodification. Additionally, there are several examples where free chains of polyubiquitin provide activating function by acting as a scaffold to recruit individual proteins into a functional, multiprotein complex. This chapter will explore specific examples of how each branch of the immune system is critically dependent on ubiquitin and/or Ubls for normal response to viral pathogens.
24. Ubiquitination and SUMOylation in HIV Infection: Friends and Foes Free download
Marta Colomer-Lluch, Sergio Castro-Gonzalez and Ruth Serra-Moreno
As intracellular parasites, viruses hijack the cellular machinery to facilitate their replication and spread. This includes favouring the expression of their viral genes over host genes, appropriation of cellular molecules, and manipulation of signalling pathways, including the post-translational machinery. HIV, the causative agent of AIDS, is notorious for using post-translational modifications to generate infectious particles. Here, we discuss the mechanisms by which HIV usurps the ubiquitin and SUMO pathways to modify both viral and host factors to achieve a productive infection, and also how the host innate sensing system uses these post-translational modifications to hinder HIV replication.
25. Ubiquitination and SUMOylation of Amyloid and Amyloid-like Proteins in Health and Disease Free download
Lenzie Ford, Luana Fioriti and Eric R. Kandel
Post-translational modifications (PTMs) play important roles in altering the structure and function of proteins. In this chapter, we focus on ubiquitination and SUMOylation of amyloidogenic proteins. We discuss the functional contributions of PTMs on proteins involved in amyloid-related diseases as well as the aberrant PTM signatures of the disease agents. In addition, we extend our discussion to the nascent field of functional amyloids, a subclass of amyloids that perform physiological functions. Here, we present examples from mammals and yeast to gain insight into physiological regulation of amyloid-like proteins.
26. Keeping Up With the Pathogens: The Role of SUMOylation in Plant Immunity
Rebecca Morrell and Ari Sadanandom
Owing to the changing, challenging pressures the plant pathogens can exert on hosts, plants require mechanisms to quickly sense and respond to them. Post-translational modifications (PTMs) provide a molecular level of control that can rapidly alter the stability, interaction and localisation of proteins. SUMO is being increasingly implicated as a critical modifier affecting plant susceptibility at all stages of pathogen disease progression. This review highlights how in pathogen-associated molecular patterns (PAMP)-triggered immunity (PTI) on pathogen detection a PAMP receptor is SUMOylated to enable downstream pathogen defence genes. In effector-triggered susceptibility (ETS) pathogens exploit the plants endogenous SUMO system to aid disease progression, injecting SUMO proteases into the plant cells. Finally, in effector-triggered immunity (ETI), many mutants in the SUMO system show increased disease resistance due to elevated levels of salicylic acid and the consequential downstream signalling of pathogen defence genes. The research presented aims to highlight the critical role SUMO plays in plant immunity, not only in SUMOylating critical pathogen defence molecules, but also indirectly by affecting important hormone signalling pathways involved in pathogen defence.
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(EAN: 9781912530120 9781912530137 Subjects: [epigenetics] [molecular biology] [molecular microbiology] )