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Cancer Metastasis Reviews Dec 2017The clinical efficacy of proteasome inhibitors in the treatment of multiple myeloma has encouraged application of proteasome inhibitor containing therapeutic... (Review)
Review
The clinical efficacy of proteasome inhibitors in the treatment of multiple myeloma has encouraged application of proteasome inhibitor containing therapeutic interventions in (pediatric) acute leukemia. Here, we summarize the positioning of bortezomib, as first-generation proteasome inhibitor, and second-generation proteasome inhibitors in leukemia treatment from a preclinical and clinical perspective. Potential markers for proteasome inhibitor sensitivity and/or resistance emerging from leukemia cell line models and clinical sample studies will be discussed focusing on the role of immunoproteasome and constitutive proteasome (subunit) expression, PSMB5 mutations, and alternative mechanisms of overcoming proteolytic stress.
Topics: Acute Disease; Animals; Bortezomib; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Leukemia; Molecular Targeted Therapy; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 29071527
DOI: 10.1007/s10555-017-9699-4 -
Cell Chemical Biology Jul 2021Proteasomes are multisubunit complexes that catalyze the majority of protein degradation in mammalian cells to maintain protein homeostasis and influence the regulation... (Review)
Review
Proteasomes are multisubunit complexes that catalyze the majority of protein degradation in mammalian cells to maintain protein homeostasis and influence the regulation of most cellular processes. The proteasome, a multicatalytic protease complex, is a ring-like structure with a narrow pore that exhibits regulated gating, enabling the selective degradation of target proteins into peptide fragments. This process of removing proteins is essential for eliminating proteins that are no longer wanted, such as unfolded or aggregated proteins. This is important for preserving cellular function relevant to brain health and disease. Recently, in the nervous system, specialized proteasomes have been shown to generate peptides with important cellular functions. These discoveries challenge the prevailing notion that proteasomes primarily operate to eliminate proteins and identify signaling-competent proteasomes. This review focuses on the structure, function, and regulation of proteasomes and sheds light on emerging areas of investigation regarding the role of proteasomes in the nervous system.
Topics: Animals; Humans; Nervous System; Proteasome Endopeptidase Complex
PubMed: 33905676
DOI: 10.1016/j.chembiol.2021.04.003 -
Annual Review of Cell and Developmental... Oct 2022While cellular proteins were initially thought to be stable, research over the last decades has firmly established that intracellular protein degradation is an active... (Review)
Review
While cellular proteins were initially thought to be stable, research over the last decades has firmly established that intracellular protein degradation is an active and highly regulated process: Lysosomal, proteasomal, and mitochondrial degradation systems were identified and found to be involved in a staggering number of biological functions. Here, we provide a global overview of the diverse roles of cellular protein degradation using seven categories: homeostasis, regulation, quality control, stoichiometry control, proteome remodeling, immune surveillance, and baseline turnover. Using selected examples, we outline how proteins are degraded and why this is functionally relevant.
Topics: Autophagy; Proteasome Endopeptidase Complex; Proteolysis; Proteome; Ubiquitination
PubMed: 35587265
DOI: 10.1146/annurev-cellbio-120420-091943 -
Experimental & Molecular Medicine Oct 2021Proteostasis is primarily a function of protein synthesis and degradation. Although the components and processes involved in intracellular proteostasis have been studied... (Review)
Review
Proteostasis is primarily a function of protein synthesis and degradation. Although the components and processes involved in intracellular proteostasis have been studied extensively, it is apparent that extracellular proteostasis is equitably crucial for the viability of organisms. The 26S proteasome, a unique ATP-dependent proteolytic complex in eukaryotic cells, contributes to the majority of intracellular proteolysis. Accumulating evidence suggests the presence of intact 20S proteasomes in the circulatory system (c-proteasomes), and similar to other plasma proteins, the levels of these c-proteasomes may vary, potentially reflecting specific pathophysiological conditions. Under normal conditions, the concentration of c-proteasomes has been reported to be in the range of ~0.2-2 μg/mL, which is ~2-4-fold lower than that of functional plasma proteins but markedly higher than that of signaling proteins. The characterization of c-proteasomes, such as their origin, structure, role, and clearance, has been delayed mainly due to technical limitations. In this review, we summarize the current perspectives pertaining to c-proteasomes, focusing on the methodology, including our experimental understanding. We believe that once the pathological relevance of c-proteasomes is revealed, these unique components may be utilized in the diagnosis and prognosis of diverse human diseases.
Topics: Eukaryotic Cells; Humans; Proteasome Endopeptidase Complex; Proteins; Proteolysis
PubMed: 34707192
DOI: 10.1038/s12276-021-00692-x -
Biological Chemistry Dec 2019Proteasomes are the principal molecular machines for the regulated degradation of intracellular proteins. These self-compartmentalized macromolecular assemblies... (Review)
Review
Proteasomes are the principal molecular machines for the regulated degradation of intracellular proteins. These self-compartmentalized macromolecular assemblies selectively degrade misfolded, mistranslated, damaged or otherwise unwanted proteins, and play a pivotal role in the maintenance of cellular proteostasis, in stress response, and numerous other processes of vital importance. Whereas the molecular architecture of the proteasome core particle (CP) is universally conserved, the unfoldase modules vary in overall structure, subunit complexity, and regulatory principles. Proteasomal unfoldases are AAA+ ATPases (ATPases associated with a variety of cellular activities) that unfold protein substrates, and translocate them into the CP for degradation. In this review, we summarize the current state of knowledge about proteasome - unfoldase systems in bacteria, archaea, and eukaryotes, the three domains of life.
Topics: ATPases Associated with Diverse Cellular Activities; Archaea; Bacteria; Molecular Chaperones; Proteasome Endopeptidase Complex; Protein Unfolding; Proteolysis; Proteostasis; Stress, Physiological
PubMed: 31665105
DOI: 10.1515/hsz-2019-0344 -
Biomolecules Aug 2023The 26S proteasome is the largest and most complicated protease known, and changes to proteasome assembly or function contribute to numerous human diseases. Assembly of... (Review)
Review
The 26S proteasome is the largest and most complicated protease known, and changes to proteasome assembly or function contribute to numerous human diseases. Assembly of the 26S proteasome from its ~66 individual polypeptide subunits is a highly orchestrated process requiring the concerted actions of both intrinsic elements of proteasome subunits, as well as assistance by extrinsic, dedicated proteasome assembly chaperones. With the advent of near-atomic resolution cryo-electron microscopy, it has become evident that the proteasome is a highly dynamic machine, undergoing numerous conformational changes in response to ligand binding and during the proteolytic cycle. In contrast, an appreciation of the role of conformational dynamics during the biogenesis of the proteasome has only recently begun to emerge. Herein, we review our current knowledge of proteasome assembly, with a particular focus on how conformational dynamics guide particular proteasome biogenesis events. Furthermore, we highlight key emerging questions in this rapidly expanding area.
Topics: Proteasome Endopeptidase Complex; Protein Conformation; Models, Molecular; Molecular Chaperones; Humans; Cryoelectron Microscopy; Proteolysis; Ubiquitin
PubMed: 37627288
DOI: 10.3390/biom13081223 -
Biomolecular Concepts Aug 2016The proteasome is a structural complex of many proteins that degrades substrates marked by covalent linkage to ubiquitin. Many years of research has shown a role for... (Review)
Review
The proteasome is a structural complex of many proteins that degrades substrates marked by covalent linkage to ubiquitin. Many years of research has shown a role for ubiquitin-proteasome-mediated proteolysis in synaptic plasticity and memory mainly in degrading synaptic, cytoplasmic and nuclear proteins. Recent work indicates that the proteasome has wider proteolytic and non-proteolytic roles in processes such as histone modifications that affect synaptic plasticity and memory. In this review, we assess the evidence gathered from neuronal as well as non-neuronal cell types regarding the function of the proteasome in positive or negative regulation of posttranslational modifications of histones, such as acetylation, methylation and ubiquitination. We discuss the critical roles of the proteasome in clearing excess histone proteins in various cellular contexts and the possible non-proteolytic functions in regulating transcription of target genes. In addition, we summarize the current literature on diverse chromatin-remodeling machineries, such as histone acetyltransferases, deacetylates, methyltransferases and demethylases, as targets for proteasomal degradation across experimental models. Lastly, we provide a perspective on how proteasomal regulation of histone modifications may modulate synaptic plasticity in the nervous system.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Epigenomics; Gene Expression Regulation; Gene Silencing; Histones; Humans; Neuronal Plasticity; Proteasome Endopeptidase Complex; Protein Binding; Protein Processing, Post-Translational; Proteolysis; Signal Transduction; Transcription, Genetic; Ubiquitin
PubMed: 27522625
DOI: 10.1515/bmc-2016-0016 -
Cellular and Molecular Life Sciences :... Sep 2016The ability of ubiquitin to form up to eight different polyubiquitin chain linkages generates complexity within the ubiquitin proteasome system, and accounts for the... (Review)
Review
The ability of ubiquitin to form up to eight different polyubiquitin chain linkages generates complexity within the ubiquitin proteasome system, and accounts for the diverse roles of ubiquitination within the cell. Understanding how each type of ubiquitin linkage is correctly interpreted by ubiquitin binding proteins provides important insights into the link between chain recognition and cellular fate. A major function of ubiquitination is to signal degradation of intracellular proteins by the 26S proteasome. Lysine-48 (K48) linked polyubiquitin chains are well established as the canonical signal for proteasomal degradation, but recent studies show a role for other ubiquitin linked chains in facilitating degradation by the 26S proteasome. Here, we review how different types of polyubiquitin linkage bind to ubiquitin receptors on the 26S proteasome, how they signal degradation and discuss the implications of ubiquitin chain linkage in regulating protein breakdown by the proteasome.
Topics: Humans; Polyubiquitin; Proteasome Endopeptidase Complex; Protein Binding; Ubiquitin; Ubiquitinated Proteins
PubMed: 27137187
DOI: 10.1007/s00018-016-2255-5 -
Cell Reports Jul 2023The 26S proteasome comprises 20S catalytic and 19S regulatory complexes. Approximately half of the proteasomes in cells exist as free 20S complexes; however, our...
The 26S proteasome comprises 20S catalytic and 19S regulatory complexes. Approximately half of the proteasomes in cells exist as free 20S complexes; however, our mechanistic understanding of what determines the ratio of 26S to 20S species remains incomplete. Here, we show that glucose starvation uncouples 26S holoenzymes into 20S and 19S subcomplexes. Subcomplex affinity purification and quantitative mass spectrometry reveal that Ecm29 proteasome adaptor and scaffold (ECPAS) mediates this structural remodeling. The loss of ECPAS abrogates 26S dissociation, reducing degradation of 20S proteasome substrates, including puromycylated polypeptides. In silico modeling suggests that ECPAS conformational changes commence the disassembly process. ECPAS is also essential for endoplasmic reticulum stress response and cell survival during glucose starvation. In vivo xenograft model analysis reveals elevated 20S proteasome levels in glucose-deprived tumors. Our results demonstrate that the 20S-19S disassembly is a mechanism adapting global proteolysis to physiological needs and countering proteotoxic stress.
Topics: Humans; Proteasome Endopeptidase Complex; Cytoplasm; Proteolysis; Mass Spectrometry
PubMed: 37384533
DOI: 10.1016/j.celrep.2023.112701 -
Biomolecules May 2019The last decade has seen accumulating evidence of various proteins being degraded by the core 20S proteasome, without its regulatory particle(s). Here, we will describe... (Review)
Review
The last decade has seen accumulating evidence of various proteins being degraded by the core 20S proteasome, without its regulatory particle(s). Here, we will describe recent advances in our knowledge of the functional aspects of the 20S proteasome, exploring several different systems and processes. These include neuronal communication, post-translational processing, oxidative stress, intrinsically disordered protein regulation, and extracellular proteasomes. Taken together, these findings suggest that the 20S proteasome, like the well-studied 26S proteasome, is involved in multiple biological processes. Clarifying our understanding of its workings calls for a transformation in our perception of 20S proteasome-mediated degradation-no longer as a passive and marginal path, but rather as an independent, coordinated biological process. Nevertheless, in spite of impressive progress made thus far, the field still lags far behind the front lines of 26S proteasome research. Therefore, we also touch on the gaps in our knowledge of the 20S proteasome that remain to be bridged in the future.
Topics: Animals; Humans; Neurons; Oxidative Stress; Proteasome Endopeptidase Complex; Proteostasis; Unfolded Protein Response
PubMed: 31100951
DOI: 10.3390/biom9050190