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Biomolecules Nov 2014The proteasome is a large self-compartmentalized protease complex that recognizes, unfolds, and destroys ubiquitylated substrates. Proteasome activities are required for... (Review)
Review
The proteasome is a large self-compartmentalized protease complex that recognizes, unfolds, and destroys ubiquitylated substrates. Proteasome activities are required for a host of cellular functions, and it has become clear in recent years that one set of critical actions of the proteasome occur on chromatin. In this review, we discuss some of the ways in which proteasomes directly regulate the structure and function of chromatin and chromatin regulatory proteins, and how this influences gene transcription. We discuss lingering controversies in the field, the relative importance of proteolytic versus non-proteolytic proteasome activities in this process, and highlight areas that require further investigation. Our intention is to show that proteasomes are involved in major steps controlling the expression of the genetic information, that proteasomes use both proteolytic mechanisms and ATP-dependent protein remodeling to accomplish this task, and that much is yet to be learned about the full spectrum of ways that proteasomes influence the genome.
Topics: Animals; Chromatin; Humans; Proteasome Endopeptidase Complex; RNA, Messenger; Transcription, Genetic
PubMed: 25422899
DOI: 10.3390/biom4041026 -
Microbiology and Molecular Biology... Mar 2017Regulated proteolysis is essential for the normal physiology of all organisms. While all eukaryotes and archaea use proteasomes for protein degradation, only certain... (Review)
Review
Regulated proteolysis is essential for the normal physiology of all organisms. While all eukaryotes and archaea use proteasomes for protein degradation, only certain orders of bacteria have proteasomes, whose functions are likely as diverse as the species that use them. In this review, we discuss the most recent developments in the understanding of how proteins are targeted to proteasomes for degradation, including ATP-dependent and -independent mechanisms, and the roles of proteasome-dependent degradation in protein quality control and the regulation of cellular physiology. Furthermore, we explore newly established functions of proteasome system accessory factors that function independently of proteolysis.
Topics: Adenosine Triphosphate; Archaea; Bacteria; Bacterial Proteins; Proteasome Endopeptidase Complex; Proteolysis
PubMed: 27974513
DOI: 10.1128/MMBR.00036-16 -
Cells Dec 2021Cell-mediated immunity is driven by antigenic peptide presentation on major histocompatibility complex (MHC) molecules. Specialized proteasome complexes called... (Review)
Review
Cell-mediated immunity is driven by antigenic peptide presentation on major histocompatibility complex (MHC) molecules. Specialized proteasome complexes called immunoproteasomes process viral, bacterial, and tumor antigens for presentation on MHC class I molecules, which can induce CD8 T cells to mount effective immune responses. Immunoproteasomes are distinguished by three subunits that alter the catalytic activity of the proteasome and are inducible by inflammatory stimuli such as interferon-γ (IFN-γ). This inducible activity places them in central roles in cancer, autoimmunity, and inflammation. While accelerated proteasomal degradation is an important tumorigenic mechanism deployed by several cancers, there is some ambiguity regarding the role of immunoproteasome induction in neoplastic transformation. Understanding the mechanistic and functional relevance of the immunoproteasome provides essential insights into developing targeted therapies, including overcoming resistance to standard proteasome inhibition and immunomodulation of the tumor microenvironment. In this review, we discuss the roles of the immunoproteasome in different cancers.
Topics: Animals; Humans; Models, Biological; Neoplasms; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Subunits
PubMed: 34944095
DOI: 10.3390/cells10123587 -
Biochemistry. Biokhimiia Mar 2023Proteasomes are highly conserved multienzyme complexes responsible for proteolytic degradation of the short-lived, regulatory, misfolded, and damaged proteins. They play... (Review)
Review
Proteasomes are highly conserved multienzyme complexes responsible for proteolytic degradation of the short-lived, regulatory, misfolded, and damaged proteins. They play an important role in the processes of brain plasticity, and decrease in their function is accompanied by the development of neurodegenerative pathology. Studies performed in different laboratories both on cultured mammalian and human cells and on preparations of the rat and rabbit brain cortex revealed a large number of proteasome-associated proteins. Since the identified proteins belong to certain metabolic pathways, multiple enrichment of the proteasome fraction with these proteins indicates their important role in proteasome functioning. Extrapolation of the experimental data, obtained on various biological objects, to the human brain suggests that the proteasome-associated proteins account for at least 28% of the human brain proteome. The proteasome interactome of the brain contains a large number of proteins involved in the assembly of these supramolecular complexes, regulation of their functioning, and intracellular localization, which could be changed under different conditions (for example, during oxidative stress) or in different phases of the cell cycle. In the context of molecular functions of the Gene Ontology (GO) Pathways, the proteins of the proteasome interactome mediate cross-talk between components of more than 30 metabolic pathways annotated in terms of GO. The main result of these interactions is binding of adenine and guanine nucleotides, crucial for realization of the nucleotide-dependent functions of the 26S and 20S proteasomes. Since the development of neurodegenerative pathology is often associated with regioselective decrease in the functional activity of proteasomes, a positive therapeutic effect would be obviously provided by the factors increasing proteasomal activity. In any case, pharmacological regulation of the brain proteasomes seems to be realized through the changes in composition and/or activity of the proteins associated with proteasomes (deubiquitinase, PKA, CaMKIIα, etc.).
Topics: Animals; Rats; Humans; Rabbits; Proteasome Endopeptidase Complex; Cytoplasm; Proteolysis; Proteome; Mammals; Neuronal Plasticity
PubMed: 37076280
DOI: 10.1134/S0006297923030033 -
Proceedings of the National Academy of... Jun 2021The 26S proteasome is the macromolecular machine responsible for the bulk of protein degradation in eukaryotic cells. As it degrades a ubiquitinated protein, the...
The 26S proteasome is the macromolecular machine responsible for the bulk of protein degradation in eukaryotic cells. As it degrades a ubiquitinated protein, the proteasome transitions from a substrate-accepting conformation (s1) to a set of substrate-processing conformations (s3 like), each stabilized by different intramolecular contacts. Tools to study these conformational changes remain limited, and although several interactions have been proposed to be important for stabilizing the proteasome's various conformations, it has been difficult to test these directly under equilibrium conditions. Here, we describe a conformationally sensitive Förster resonance energy transfer assay, in which fluorescent proteins are fused to Sem1 and Rpn6, which are nearer each other in substrate-processing conformations than in the substrate-accepting conformation. Using this assay, we find that two sets of interactions, one involving Rpn5 and another involving Rpn2, are both important for stabilizing substrate-processing conformations. Mutations that disrupt these interactions both destabilize substrate-processing conformations relative to the substrate-accepting conformation and diminish the proteasome's ability to successfully unfold and degrade hard-to-unfold substrates, providing a link between the proteasome's conformational state and its unfolding ability.
Topics: Fluorescence Resonance Energy Transfer; Green Fluorescent Proteins; Models, Molecular; Mutation; Proteasome Endopeptidase Complex; Protein Conformation; Protein Unfolding
PubMed: 34161281
DOI: 10.1073/pnas.2101004118 -
Journal of Clinical Immunology Apr 2024The ubiquitin-proteasome system (UPS) has a critical role in post-translational protein modification that is essential for the maintenance of all cellular functions,... (Review)
Review
The ubiquitin-proteasome system (UPS) has a critical role in post-translational protein modification that is essential for the maintenance of all cellular functions, including immune responses. The proteasome complex is ubiquitously expressed and is responsible for degradation of short-lived structurally abnormal, misfolded and not-needed proteins that are targeted for degradation via ubiquitin conjugation. Over the last 14 years, an increasing number of human diseases have been linked to pathogenic variants in proteasome subunits and UPS regulators. Defects of the proteasome complex or its chaperons - which have a regulatory role in the assembly of the proteasome - disrupt protein clearance and cellular homeostasis, leading to immune dysregulation, severe inflammation, and neurodevelopmental disorders in humans. Proteasome-associated diseases have complex inheritance, including monogenic, digenic and oligogenic disorders and can be dominantly or recessively inherited. In this review, we summarize the current known genetic causes of proteasomal disease, and discuss the molecular pathogenesis of these conditions based on the function and cellular expression of mutated proteins in the proteasome complex.
Topics: Humans; Proteasome Endopeptidase Complex; Syndrome; Ubiquitin
PubMed: 38578475
DOI: 10.1007/s10875-024-01692-y -
BioEssays : News and Reviews in... Jul 2017The segregation of homologous chromosomes in meiosis depends on their ability to locate one another in the nucleus and establish a physical association through crossing... (Review)
Review
The segregation of homologous chromosomes in meiosis depends on their ability to locate one another in the nucleus and establish a physical association through crossing over. A tightly regulated number of crossovers (COs) emerges following repair of induced DNA double-strand breaks by homologous recombination (HR), but the process of how HR intermediates transition into COs is still poorly understood. Two recent studies by Ahuja et al. and Rao et al. have revealed a role for chromosomally localized proteasomes in choreographing both homologous chromosome pairing and the evolution of HR intermediates into segregation-competent COs. Using chemical inhibition of the proteasome and mutant analysis, the collective data reveal conserved functions for both the proteasome and a family of E3 ligases that can direct or compete with its activity in ensuring CO formation. Here, we review these findings and the impact of the discovery that protein modification dynamics and proteasomal activity cooperate to regulate key meiotic processes.
Topics: Animals; Chromosome Segregation; Crossing Over, Genetic; DNA Breaks, Double-Stranded; DNA Repair; Homologous Recombination; Humans; Meiosis; Proteasome Endopeptidase Complex
PubMed: 28590593
DOI: 10.1002/bies.201700038 -
Cells Feb 2023RUNX3 is a transcription factor with regulatory roles in cell proliferation and development. While largely characterized as a tumor suppressor, RUNX3 can also be... (Review)
Review
RUNX3 is a transcription factor with regulatory roles in cell proliferation and development. While largely characterized as a tumor suppressor, RUNX3 can also be oncogenic in certain cancers. Many factors account for the tumor suppressor function of RUNX3, which is reflected by its ability to suppress cancer cell proliferation after expression-restoration, and its inactivation in cancer cells. Ubiquitination and proteasomal degradation represent a major mechanism for the inactivation of RUNX3 and the suppression of cancer cell proliferation. On the one hand, RUNX3 has been shown to facilitate the ubiquitination and proteasomal degradation of oncogenic proteins. On the other hand, RUNX3 can be inactivated through the ubiquitin-proteasome system. This review encapsulates two facets of RUNX3 in cancer: how RUNX3 suppresses cell proliferation by facilitating the ubiquitination and proteasomal degradation of oncogenic proteins, and how RUNX3 is degraded itself through interacting RNA-, protein-, and pathogen-mediated ubiquitination and proteasomal degradation.
Topics: Humans; Proteasome Endopeptidase Complex; Ubiquitin; Ubiquitination; Neoplasms; Core Binding Factor Alpha 3 Subunit
PubMed: 36899853
DOI: 10.3390/cells12050717 -
Cells Nov 2021Numerous cellular processes are controlled by the proteasome, a multicatalytic protease in the cytosol and nucleus of all eukaryotic cells, through regulated protein... (Review)
Review
Numerous cellular processes are controlled by the proteasome, a multicatalytic protease in the cytosol and nucleus of all eukaryotic cells, through regulated protein degradation. The immunoproteasome is a special type of proteasome which is inducible under inflammatory conditions and constitutively expressed in hematopoietic cells. MECL-1 (β2i), LMP2 (β1i), and LMP7 (β5i) are the proteolytically active subunits of the immunoproteasome (IP), which is known to shape the antigenic repertoire presented on major histocompatibility complex (MHC) class I molecules. Furthermore, the immunoproteasome is involved in T cell expansion and inflammatory diseases. In recent years, targeting the immunoproteasome in cancer, autoimmune diseases, and transplantation proved to be therapeutically effective in preclinical animal models. However, the prime function of standard proteasomes and immunoproteasomes is the control of protein homeostasis in cells. To maintain protein homeostasis in cells, proteasomes remove proteins which are not properly folded, which are damaged by stress conditions such as reactive oxygen species formation, or which have to be degraded on the basis of regular protein turnover. In this review we summarize the latest insights on how the immunoproteasome influences protein homeostasis.
Topics: Animals; Humans; Models, Biological; Oxidation-Reduction; Proteasome Endopeptidase Complex; Proteolysis; Proteostasis; Ubiquitination
PubMed: 34831438
DOI: 10.3390/cells10113216 -
Medicinal Research Reviews Sep 2018Proteins actively participate in a wide range of cellular physiological functions. But aggregation of proteins results in cytotoxicity, and unwanted aggregation of... (Review)
Review
Proteins actively participate in a wide range of cellular physiological functions. But aggregation of proteins results in cytotoxicity, and unwanted aggregation of misfolded proteins often causes many diseases. During abnormal protein aggregation events, cells try to cope against such deleterious consequences because of the remarkable functional attempts of two distinct proteolytic mechanisms. These tightly regulative and signaling mechanisms are autophagy pathway and ubiquitin proteasome system. Proteasome complex system holds the elimination capacity of intracellular aberrant protein aggregation. Despite the considerable progress that has been achieved, which elucidates wide function and diverse roles of proteasome system, still several crucial problems remain unanswered. For example, how the complex proteasomes assembly and their interactive pathways determine the precise sense of several proteotoxic insults, which can severely affect the cell survival and homeostasis? The specific degradation of various aberrant proteins that can disturb cellular homeostasis is achieved by proper proteasome functionality, which is yet another unclear and critical challenge. Therefore, a better understanding of the various cellular signaling mechanisms composing the proteasome machinery carries broad therapeutic implications linked with proteopathies. This article signifies the urgent need, which is now crucial for us to improve our understanding of the proteasome architecture, structure, and functions that span multiple level strategies from the molecular level to the cellular level. This systematic in-depth information of proteasome may be helpful in the near future to design a new molecular framework based on intrinsic and extrinsic cellular mechanisms that drive the assembly of proteasome to induce cellular survival against proteostasis imbalance and disease conditions.
Topics: Animals; Disease; Homeostasis; Humans; Proteasome Endopeptidase Complex; Proteostasis; Stress, Physiological; Ubiquitin
PubMed: 29719055
DOI: 10.1002/med.21502