Special Issue "Ubiquitination in Health and Disease"
A special issue of Cells (ISSN 2073-4409).
Deadline for manuscript submissions: 10 August 2018
Ubiquitination is a post-translational modification process that controls the degradation, signaling and activity of many, if not all, cellular proteins. Ubiquitination needs to be finely tuned and is catalyzed and controlled by several players: ubiquitin; the E1 ubiquitin activating enzyme, the E2 ubiquitin conjugating enzymes, the E3 ubiquitin ligases, which compose the ubiquitination cascade; the deubiquitination enzymes that reverse the modification; and the proteins that recognize the ubiquitination code and translate the signal. Substrates can be modified with a single ubiquitin peptide, in one or multiple sites, or with a poly-ubiquitin chain. The topology of the built ubiquitin chain determines the fate of the targeted substrate. In cells also free poly-ubiquitin chains, which are not conjugated to any target protein, can be synthesized. In recent years, considerable progress has been made in the understanding the molecular action of ubiquitin in signaling pathways and how alterations in the ubiquitin system lead to the development of several human diseases from cancer, metabolic syndromes, neurodegenerative diseases, inflammatory disorders, and rare genetic disorders.
In this Special Issue of Cells, we invite your contributions, either in the form of original research articles or reviews addressing the expanding field of mechanistic and functional insights into the physiological and pathological role of specific ubiquitination pathways and components.Prof. Germana Meroni
Dr. Giuseppe Merla
Manuscript Submission Information
Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.
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- E3 ubiquitin ligases
- E2 ubiquitin conjugating enzymes
- ubiquitin binding domains
The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.
Tentative title: De-ubiquitination in the regulation of cell function and disease
Authors: Areej Alzahrani 1, William R. Critchley 1, Ian C. Zachary 2, Michael A. Harrison 3, Elton Zeqiraj 4, Sreenivasan Ponnambalam 1
1 Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, University of Leeds, UK;
2 Centre for Cardiovascular Biology & Medicine, Rayne Building, University College London, UK;
3 School of Biomedical Sciences, University of Leeds, UK;
4 Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, UK.
Tentative title: The Drosophila HUWE1 Ubiquitin Ligase Regulates Endoreplication, and Salivary Gland Development
Authors: Yifat Yanku, Eliya Bitman, Yaniv Zohar, Norman Zilke, Martin Eilers, and Amir Orian
Tentative abstract: HECT (E6-AP carboxyl terminus)-type E3 ubiquitin-ligases regulate diverse cellular processes during development and in adult tissues in metazoans. A highly evolutionary conserved HECT ubiquitin ligases is HUWE1 (known also as HECTh9, MULE, LASU1, ARF-BP1). In cancer, the function of HUWE1 is context dependent. It regulates cell proliferation, cell death, the response to DNA damage, mitochondria homeostasis, as well as NF-kB and JNK signaling pathways. However, the developmental role(s) of HUWE1 are less well understood. Studying the role of dHUWE1 in Drosophila we report that HUWE1 is critical for the endoreplication, the development of salivary gland, and the timing of its physiological degeneration. Remarkably, we show that these functions of dHUWE1 are intimately associated with Myc, p53 and the JNK pathway in vivo.
Tentative title: Ubiquitin Regulation: The Histone Modifying Enzymes's Story
Author: Yadi Wu
Affiliation: College of Medicine, University of Kentucky, Lexington, KY, USA
Tentative abstract: Histone post-translational modifications (PTMs) contribute to many fundamental aspects through regulating chromatin structure and gene transcriptional activity. These modifications are highly dynamic and tightly controlled, with many enzymes dedicated to their addition and removal. Interestingly, these modification enzymes are also fine-tuned and precisely regulated at the level of protein turnover by ubiquitin-proteasonal processing. Here, we focuses on the recent progress on mechanism for ubiquitin regulation of histone modification enzymes including ubiquitin proteasomal degradation and its reversal process--deubiquitination. We will also discuss the potential pathophysiological significance of this process.
Tentative title: Ubiquitination and muscle cachexia/sarcopenia
Author: Daniel Taillandier
Abstract: Skeletal muscle mass is reduced during many diseases or physiological situations (disuse, aging), which ends up to decreased strength and increased mortality. Muscle mass is mainly controlled by the ubiquitin-proteasome system (UPS). Hundreds of ubiquitinating enzymes target their dedicated substrates for subsequent degradation, which include E2 and E3 enzymes. We recently demonstrated that MuRF1, an E3 ubiquitin ligase known to bind to sarcomeric proteins (telethonin, α-actin, myosins) during catabolic situations, interacts with 5 different E2 enzymes and that these E2-MuRF1 couples are able to target telethonin for degradation. Amongst the E2s interacting with MuRF1, E2E1 is peculiar as the presence of telethonin is necessary for optimal MuRF1-E2E1 interaction.
In this work, we focused on E2E1 and its putative role in skeletal muscle. We found that E2E1 was able to increase a-actin degradation in heterologous HEK293T cells. By contrast, Myosin Heavy Chain was not affected by the presence of E2E1, suggesting that the MuRF1-E2E1 couple exhibit target preferences. We further investigated the role of E2E1 in C2C12 myotubes subjected to a catabolic state (Dexamethasone treatment) and found that knock-down of E2E1 was not sufficient for preserving muscle mass, which suggests that E2E1 is dispensable for the development of muscle atrophy. However, we found that E2E1 expression was restricted to type IIa and type IIx muscle fibers and excluded from type IIb fibers. This strongly suggests that E2E1 targets are fiber-specific and may be strongly linked to the contractile and metabolic properties of the skeletal muscle.
Tentative title: The effect of neurotoxin MPTP and neuroprotector isatin on the profile of ubiquitinated brain mitochondrial proteins
Author: Alexei Medvedev
Abstract: Mitochondria play an important role in molecular mechanisms of adaptive changes of the brain that occur in response to development of pathological disorders. Mitochondria are a crucial target for actions of neurotoxins, causing symptoms of Parkinson’s disease in various experimental animal models, and also neuroprotectors. In this context there is evidence that mitochondrial dysfunction induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) influences functioning of the ubiquitin-proteasomal system (UPS) responsible for selective proteolytic degradation of proteins from various intracellular compartments (including mitochondria) and neuroprotective effects of certain antiparkisonian agents (monoamine oxidase inhibitors) may be associated with their effects on UPS.
In this study we have investigated the effect of the neurotoxin MPTP, neuroprotector isatin and their combination of the profile of ubiquitinated brain mitochondrial proteins. The development of movement disorders induced by MPTP administration was accompanied by minor changes in the number of ubiquitinated mitochondrial proteins but dramatic qualitative changes. Pretreatment with the neuroprotector isatin decreased manifestations of MPTP-induced parkinsonism and had a significant qualitative impact on the profile of ubiquitinated mitochondrial proteins. Administration of isatin alone to intact mice also influenced the profile of ubiquitinated mitochondrial proteins. Thus the pool of ubiquitinated mitochondrial proteins is significantly influenced by both neurotoxins and neuroprotectors. Biological importance of these changes in discussed.
Tentative title: Ubiquitination-deubiquination during DNA replication initiation
Author: Raimundo Freire
Abstract: Eukaryotic cells divide accomplishing a program of events in which the replication of the genome is a fundamental part. To ensure that the genome of the mother cell is accurately passed on to the daughter cells, DNA replication occurs only once per cell cycle and is strictly regulated by numerous pathways. In this, a key step is the initiation of DNA replication in which regions of DNA are marked as competent to replicate. Moreover, initiation of DNA replication needs to be coordinated with other cell cycle processes to ensure genomic integrity. At the molecular level, initiation of DNA replication relies, among other mechanisms, on post-translational modifications, including the ubiquitin conjugation and hydrolysis. One example is the precise control of the levels of the DNA replication initiation protein Cdt1 and its inhibitor Geminin by ubiquitination-proteasomal degradation, during the cell cycle. This control guarantees that DNA replication occurs with the right timing during the cell cycle and avoids re-replications events. Here we review the role of ubiquitin signalling in DNA replication initiation and discuss the open questions in the field.