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.
Type of Paper: Review
Title: Molecular action of Proteasome regulators: significance for efficient tumor therapy
Authors: Mohamed Hassan 1,2,3
Affiliations: 1 Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA; 2 Institut National de la Santé et de la Recherche Médicale, U 977, France;
3 Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France; E-Mail: email@example.com (M.H.)
Abstract: The structure and function of the proteasome have been intensively studied in the last three decades. Proteasome is multi-subunit protein complex that, in collaboration with ubiquitin, can mediate the regulation of an energy-dependent proteolytic process in eukaryotic cells. Proteosome is an ambitious 2.5-MDa protein degradation system containing a proteolytic core particle and two terminal regulatory particles. The core particle consists of two outer α rings and two inner β rings that finally form seven structurally similar α and β subunits. The inner surface of the core particle is characterized by its catalytic threonine residues that are characterized by their caspase, trypsin and chymotrypsin-like activities. While, the regulatory particles are responsible for the recognition of the polyubiquitylated substrate proteins to mediate consequently their deubiquitylating, unfolding, and translocation into the interior of the core particle for degradation. Thus, the highlight of the mechanistic role of proteasome regulators, both inhibitors and activators, during the course of tumortherapy may help improve the outcome of tumor treatment. In this review, we will focus on the molecular action of proteasome regulators in the modulation of tumor resistance and response to current therapy.
Type of Paper: Review
Title: Regulating the 20S proteasome ubiquitin independent degradation pathway
Author: Gili Ben-Nissan and Michal Sharon*
Affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel; E-Mail: firstname.lastname@example.org (M.S.)
Abstract: Both cellular homeostasis and regulation of cellular functions depend on the finely orchestrated degradation of proteins. The ubiquitin-dependent 26S proteasomal degradation pathway most likely represents the primary cellular means of protein turnover; however, it is becoming increasingly clear that proteins can also be degraded via an ubiquitin-independent route, mediated by the 20S proteasome. Degradation by the 20S proteasome is a passive process that does not require ubiquitin tagging or the presence of the 19S regulatory particle, rather, it relies on the inherent disorder of the protein being degraded. Thus, proteins that contain unstructured regions due to aging, mutation, or oxidation, as well as naturally unfolded proteins, are susceptible to 20S degradation. Interestingly, proteins involved in oncogenesis and tumor suppression comprise the majority of the known 20S proteasome substrates; for example the tumor suppressors p53, p73, and retinoblastoma protein (Rb), the proto-oncoprotein c-Fos, as well as the cell cycle regulators p21 and p27, have been identified as substrates of 20S proteasomes. Here, we provide an overview of mechanisms regulating the function of the 20S proteasome and discuss how their manipulation might provide therapeutic benefits in the future.
Type of Paper: Article
Title: Differential Expression of Proteasome Subunits and Functional Activity during Neonatal Development
Author: Elaine Petrof
Affiliation: Dept.Medicine/Infectious Diseases, Gastrointestinal Diseases Research Unit,Queens University & Kingston General Hospital,76 Stuart Street, GIDRU wing, Kingston, ON, K7L 2V7, Canada; E-Mail: email@example.com (E.P.)
Abstract:Proteasomes regulate many essential cellular processes by degrading intracellular proteins. While aging is known to be associated with dysfunction of the proteasome, there are few reports detailing activity and function of proteasomes in the early stages of life. To elucidate the function and development of mammalian proteasomes, proteasomes were purified from rat small intestine, spleen and liver. The developmental expression of core, regulatory and immunoproteasome subunits was analyzed by immunblotting and proteasome catalytic function was determined by fluorogenic enzymatic assays. The expression of subunits associated with the primitive 20S barrel (β5 and β2 subunits) were found to be present in very early developmental stages. A gradual developmental progression with increased expression of regulatory and immunoproteasome subunits (Rpt5, β1i, β5i subunits) was observed over time. Our studies demonstrated a developmental pattern to proteasome activity and subunit expression, suggesting that the more primitive forms of proteasomes may predominate at early gestation points.
Type of Paper: Article
Title: Chaperoning Proteins for Destruction: Diverse Roles of Heat Shock Proteins in Targeting Misfolded Proteins to the Proteasome
Authors: A. Shiber and Tommer Ravid
Affiliation: Dept. of Biological Chemistry, Room 1-523, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat-Ram, Jerusalem 91904, Israel.; E-Mail: firstname.lastname@example.org (T.R.)
Abstract: Molecular chaperones were originally discovered as heat shock-induced proteins that facilitate proper folding of proteins with non-native conformations. While the function of chaperones in protein folding has been well documented over the last four decades, more recent studies have shown that chaperones are also necessary for the clearance of terminally misfolded proteins by the ubiquitin-proteasome system. In this capacity, chaperones protect misfolded degradation substrates from spontaneous aggregation, facilitate their recognition by the ubiquitin ligation machinery and finally shuttle the ubiquitylated substrates to the proteasome. The physiological importance of these functions is manifested by inefficient proteasomal degradation and the accumulation of protein aggregates during ageing or in certain neurodegenerative diseases, when chaperone levels decline. In this review we focus on the diverse roles of stress-induced chaperones in targeting misfolded proteins to the proteasome and the consequences of their compromised activity. We further discuss the implications of these findings to the identification of new therapeutic targets for the treatment of amyloid diseases.
Type of Paper: Review
Title: Polyubiquitinated proteins and proteasome rich cytoplasmic structures: Identification, natural history, role in cell biology and pathology
Authors: Enrico Solcia 1,2, P. Sommi 1, V. Necchi 1,3, A. Vitali 1, R. Manca 2, V. Ricci 1
Affiliations: 1Department of Molecular Medicine, University of Pavia, Pavia, Italy;
2Pathologic Anatomy Unit, IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy; 3Centro Grandi Strumenti, University of Pavia, Pavia, Italy; E-Mail: email@example.com (E.S.)
Abstract: Cytoplasmic structures showing selective concentration of polyubiquitinated proteins and proteasome have been described in various epithelial, hematopoietic, mesenchymal and neural cells in vitro or in fetal tissues, as well as in chronically infected, mutated preneoplastic and neoplastic tissues. These cytoplasmic structures show distinctive ultrastructural organization (particles-rich cytoplasmic structure or PaCS) and cytochemical patterns, and their formation can be induced in vitro in dendritic or natural killer cells by trophic factors and interleukins treatment. Such structures originate in close connection with ribosomes, and as a result of their growth, the cytoskeleton and other surrounding organelles are usually dislocated outside their core. Interestingly, these particulate cytoplasmic structures are often found to fill cytoplasmic blebs forming proteasome and polyubiquitinated proteins-discharging vesicles, called ectosomes, which are found to detach from the cell and freely float in the extracellular space. To clearly point out the importance of the polyubiquitinated proteins and proteasome containing cytoplasmic structures their role in cell biology and pathology will be carefully analyzed.
Type of Paper: Review
Title: Ubiquitin-Proteasome System (UPS) and Initiation of Gene Transcription
Authors: Geetha Durairaj and Peter Kaiser *
Affiliation: University of California, Irvine, Department of Biological Chemistry, College of Medicine, 240D Med Sci I, Irvine, CA 92697-1700, USA; E-Mail: firstname.lastname@example.org (G.D.); email@example.com (P.K.)
Abstract: Transcription activation is the foremost step of gene expression and is modulated by various factors that act in synergy. Misregulation of this process and its associated factors is linked to grave anomalies and hence calls for a strong regulatory control. In recent years, growing evidence has highlighted the ubiquitin-proteasome system (UPS) as an important contributor to the regulation of transcription initiation. Well known for its role in protein destruction, its contribution to protein synthesis was initially viewed with skepticism. However, studies over the past years have established the role of UPS in transcription initiation through its proteolytic as well as non-proteolytic activities. Pertaining to such mechanistically contrastive roles of UPS in transcription activation, in this review, we discuss the advancements made so far in understanding the connections between transcription initiation and the ubiquitin-proteasome system.
Type of Paper: Review
Title: Mathematical Models are Key to Understanding the Complexity of the Proteasome Regulatory System
Author: Michele Mishto
Affiliation: Department of Experimental Pathology, University of Bologna, Bologna, Italy, Interdepartmental Center for Studies on Biophysics, Bioinformatics and Biocomplexity ‘L. Galvani’ (CIG), Bologna, Italy, Institute of Biochemistry, Medical Faculty Charité, Berlin, Germany; E-Mail: firstname.lastname@example.org (M.M.)
Abstract: Proteasome is a key protease involved in a variety of processes from the clearance of damaged proteins to the presentation of antigens to CD8+ T lymphocytes. Which cleavage sites are used within the target proteins and how fast these proteins are degraded have a wide impact on immune system function and on several cellular metabolism processes. The regulation of proteasome activity may occur by different mechanisms such as the substitution of the catalytic subunits, the binding of regulatory complexes to proteasome gates and the proteasome conformational modifications triggered by the target protein itself. Mathematical models are perhaps the best solution to analyze and potentially predict the complex interaction of proteasome regulatory mechanisms and the final outcome in matter of the protein degradation rate and MHC class I epitope generation. The few pioneering attempts that have been done to mathematically model proteasome activity, cleavage preference variation and how they are modified by one of these regulatory mechanisms are here reviewed.
Type of Paper: Review
Title: Viral Rewiring of Cullin E3 Ligases and Proteasomal Activity
Authors: Cathal Mahon 1 and Elah Pick 2,*
1 Department of Pharmaceutical Chemistry, University of California San Francisco (UCSF), San Francisco, California, USA
2Department of Biology and Environment, Faculty of natural Sciences, the university of Haifa, Israel; E-Mails: email@example.com (C.M.); firstname.lastname@example.org (E.P.)
Abstract: The ability of viruses to subvert host pathways is critical in disease pathogenesis. Work over the past decade has uncovered a critical role for the ubiquitin proteasome system in counteracting host innate immune factors during viral infection. This counteraction is often achieved by viral proteins sequestering host ubiquitin E3 ligases, and especially members of the cullin-RING E3 ligase (CRL) family. This is achieved by the expression of viral proteins that act as co-factors of cullin-adaptor proteins, thereby re-directing them to degrade host targets, often exclusively. Removal of these host targets creates a more amenable cellular environment for viral propagation. To date a small number of targets have been identified, almost all of which are degraded via a Cullin E3 ligase - proteasomal pathway. Substantial effort within the field is ongoing to understanding both the extent of host proteins targeted in this fashion, and the underlying mechanisms driving their proteasomal degradation. Elucidation of these targets and mechanisms would provide an appealing anti-viral therapeutic opportunity. This review is focused on how viruses perturb host Cullin E3 ligases focusing on substrate sequestration and regulation of E3 activity. In addition we will discuss the poorly understood subsequent proteasomal targeting and turnover of viral substrates.