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Annual Review of Microbiology 2015Interest in bacterial proteasomes was sparked by the discovery that proteasomal degradation is required for the pathogenesis of Mycobacterium tuberculosis, one of the... (Review)
Review
Interest in bacterial proteasomes was sparked by the discovery that proteasomal degradation is required for the pathogenesis of Mycobacterium tuberculosis, one of the world's deadliest pathogens. Although bacterial proteasomes are structurally similar to their eukaryotic and archaeal homologs, there are key differences in their mechanisms of assembly, activation, and substrate targeting for degradation. In this article, we compare and contrast bacterial proteasomes with their archaeal and eukaryotic counterparts, and we discuss recent advances in our understanding of how bacterial proteasomes function to influence microbial physiology.
Topics: Archaea; Bacterial Proteins; Eukaryotic Cells; Mycobacterium; Mycobacterium tuberculosis; Proteasome Endopeptidase Complex; Proteolysis
PubMed: 26488274
DOI: 10.1146/annurev-micro-091014-104201 -
Biological Reviews of the Cambridge... Nov 2018Proteasomes are responsible for the turnover of most cellular proteins, and thus are critical to almost all cellular activities. A substrate entering the proteasome must... (Review)
Review
Proteasomes are responsible for the turnover of most cellular proteins, and thus are critical to almost all cellular activities. A substrate entering the proteasome must first bind to a substrate receptor. Substrate receptors can be classified as ubiquitin receptors and non-ubiquitin receptors. The intrinsic ubiquitin receptors, including proteasome regulatory particle base subunits 1, 10 and 13 (Rpn1, Rpn10, and Rpn13), determine the capability of the proteasome to recognize a ubiquitin chain, and thus provide selectivity for the 26S proteasome. However, the non-ubiquitin receptors, including proteasome activator 200 (PA200) and PA28γ, have received great attention due to their remarkable compensatory roles relative to canonical ubiquitin-mediated proteasomal degradation. Herein we review recent advances in understanding the contributions of these substrate receptors to proteasomal degradation, and introduce their substrates and interacting factors. We also provide insights into their biological functions related to spermatogenesis, immune responses, cellular homeostasis, and tumour development. Finally, we summarize advances in developing small-molecule inhibitors of these substrate receptors and discuss their potential as drug targets.
Topics: Animals; Humans; Proteasome Endopeptidase Complex; Protein Binding; Ubiquitinated Proteins; Ubiquitins
PubMed: 29732666
DOI: 10.1111/brv.12419 -
Biomolecules Apr 2022Proteasomes are traditionally considered intracellular complexes that play a critical role in maintaining proteostasis by degrading short-lived regulatory proteins and... (Review)
Review
Proteasomes are traditionally considered intracellular complexes that play a critical role in maintaining proteostasis by degrading short-lived regulatory proteins and removing damaged proteins. Remarkably, in addition to these well-studied intracellular roles, accumulating data indicate that proteasomes are also present in extracellular body fluids. Not much is known about the origin, biological role, mode(s) of regulation or mechanisms of extracellular transport of these complexes. Nevertheless, emerging evidence indicates that the presence of proteasomes in the extracellular milieu is not a random phenomenon, but rather a regulated, coordinated physiological process. In this review, we provide an overview of the current understanding of extracellular proteasomes. To this end, we examine 143 proteomic datasets, leading us to the realization that 20S proteasome subunits are present in at least 25 different body fluids. Our analysis also indicates that while 19S subunits exist in some of those fluids, the dominant proteasome activator in these compartments is the PA28α/β complex. We also elaborate on the positive correlations that have been identified in plasma and extracellular vesicles, between 20S proteasome and activity levels to disease severity and treatment efficacy, suggesting the involvement of this understudied complex in pathophysiology. In addition, we address the considerations and practical experimental methods that should be taken when investigating extracellular proteasomes. Overall, we hope this review will stimulate new opportunities for investigation and thoughtful discussions on this exciting topic that will contribute to the maturation of the field.
Topics: Cytoplasm; Extracellular Vesicles; Proteasome Endopeptidase Complex; Proteins; Proteomics
PubMed: 35625547
DOI: 10.3390/biom12050619 -
FASEB Journal : Official Publication of... Jun 2019A majority of thousands of intracellular mammalian proteins are recognized by proteasome only being conjugated with ubiquitin (Ub), representing a universal degradation...
A majority of thousands of intracellular mammalian proteins are recognized by proteasome only being conjugated with ubiquitin (Ub), representing a universal degradation signal operated by the ubiquitination system. Ub-independent proteasome targeting is rationalized by the existence of 2 types of direct proteasome signals (DPSs), specific amino acid sequences or post-translational modifications, which are recognized by proteasome regulatory subunits. Historically, the first type was shown to exist in ornithine decarboxylase, whereas acetylation of core histones recently was reported as a second type of DPS. Here we declare a third type, representing charge-mediated DPS. This discovered DPS may be classified as a monopartite composition- but not sequence-dependent element of ∼70 Å in length enriched in basic and flexible amino acids. This type of degradation signal, which may be provided by cationic chemicals, is most efficiently engaged by proteasomes capped with regulator (REG)α or REGγ in an ATP-independent manner. Taken together, our findings suggest a novel modality of proteasome-substrate interrelation bypassing ubiquitination.-Kudriaeva, A., Kuzina, E. S., Zubenko, O., Smirnov, I. V., Belogurov, A. Charge-mediated proteasome targeting.
Topics: Animals; Autoantigens; Cations; HEK293 Cells; Humans; Liver; Mice, Inbred BALB C; Myelin Basic Protein; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Proteolysis; Substrate Specificity; Ubiquitin; Ubiquitination
PubMed: 30811957
DOI: 10.1096/fj.201802237R -
Current Genetics Feb 2018Profound knowledge is available for the structure, function and regulation of proteasomes, the key proteases for ubiquitin-dependent protein degradation in dividing... (Review)
Review
Profound knowledge is available for the structure, function and regulation of proteasomes, the key proteases for ubiquitin-dependent protein degradation in dividing cells. Far less understood are proteasome structure and function in quiescence, the resting phase of our body's cells, as in yeast cells grown to stationary phase. In quiescent yeast proteasomes exit the nucleus and accumulate in cytoplasmic protein droplets, called proteasome storage granules (PSG). PSG-like structures also exist in non-dividing mammalian cells suggesting that the mechanism underlying PSG organization is conserved from yeast to human. The PSG has physiological significance as it protects yeast cells against stress and confers fitness during aging. The molecular architecture of PSG remains an enigma, since PSG freely move as spherical units without being surrounded by membranes through the cytoplasm. They rapidly resolve with the resumption of cell proliferation and proteasomes reenter the nucleus. Our systems biology and biochemical data revealed that PSG are mainly composed of proteasomes and free ubiquitin. Often intrinsically disordered proteins undergo liquid phase separations, allowing soluble proteins to condense into protein droplets in an aqueous solution. The question is which proteins and factors nucleate PSG formation, since proteasomes composed of folded subunits are able to degrade intrinsically disordered proteins.
Topics: Cell Cycle; Cytoplasmic Granules; Models, Biological; Proteasome Endopeptidase Complex; Proteolysis; Ubiquitin; Yeasts
PubMed: 28835998
DOI: 10.1007/s00294-017-0739-y -
Sub-cellular Biochemistry 2019Proteasomes are a class of protease that carry out the degradation of a specific set of cellular proteins. While essential for eukaryotic life, proteasomes are found... (Review)
Review
Proteasomes are a class of protease that carry out the degradation of a specific set of cellular proteins. While essential for eukaryotic life, proteasomes are found only in a small subset of bacterial species. In this chapter, we present the current knowledge of bacterial proteasomes, detailing the structural features and catalytic activities required to achieve proteasomal proteolysis. We describe the known mechanisms by which substrates are doomed for degradation, and highlight potential non-degradative roles for components of bacterial proteasome systems. Additionally, we highlight several pathways of microbial physiology that rely on proteasome activity. Lastly, we explain the various gaps in our understanding of bacterial proteasome function and emphasize several opportunities for further study.
Topics: Bacteria; Bacterial Proteins; Proteasome Endopeptidase Complex; Proteolysis
PubMed: 31939157
DOI: 10.1007/978-3-030-28151-9_11 -
Biochimica Et Biophysica Acta.... Mar 2021Accumulating evidence arising from numerous clinical studies indicate that assembled and functional 20S proteasome complexes circulate freely in plasma. Elevated levels... (Review)
Review
Accumulating evidence arising from numerous clinical studies indicate that assembled and functional 20S proteasome complexes circulate freely in plasma. Elevated levels of this core proteolytic complex have been found in the plasma of patients suffering from blood, skin and solid cancers, autoimmune disorders, trauma and sepsis. Moreover, in various diseases, there is a positive correlation between circulating 20S proteasome (c20S) levels and treatment efficacy and survival rates, suggesting the involvement of this under-studied c20S complex in pathophysiology. However, many aspects of this system remain enigmatic, as we still do not know the origin, biological role or mechanisms of extracellular transport and regulation of c20S proteasomes. In this review, we provide an overview of the current understanding of the c20S proteasome system and discuss the remaining gaps in knowledge.
Topics: Animals; Autoimmune Diseases; Burns; Hematologic Neoplasms; Humans; Neoplasms; Proteasome Endopeptidase Complex; Proteolysis; Sepsis
PubMed: 33338594
DOI: 10.1016/j.bbadis.2020.166041 -
Biomolecules Nov 2021The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome... (Review)
Review
The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate degradation with small molecules may therefore be a valuable strategy for the treatment of various neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's diseases. In this review, we discuss the structure of proteasome and how proteasome's proteolytic activity is associated with aging and various neurodegenerative diseases. We also summarize various classes of compounds that are capable of enhancing, directly or indirectly, proteasome-mediated protein degradation.
Topics: Aging; Humans; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Folding; Proteolysis; Small Molecule Libraries
PubMed: 34944433
DOI: 10.3390/biom11121789 -
Molecular Cell Apr 2022Protein degradation occurs through proteasomal, endosomal, and lysosomal pathways. Technological advancements have allowed for the determination of protein copy numbers... (Review)
Review
Protein degradation occurs through proteasomal, endosomal, and lysosomal pathways. Technological advancements have allowed for the determination of protein copy numbers and turnover rates on a global scale, which has provided an overview of trends and rules governing protein degradation. Sharper chemical and gene-editing tools have enabled the specific perturbation of each degradation pathway, whose effects on protein dynamics can now be comprehensively analyzed. We review major studies and innovation in this field and discuss the interdependence between the major pathways of protein degradation.
Topics: Autophagy; Endosomes; Lysosomes; Proteasome Endopeptidase Complex; Proteolysis
PubMed: 35305310
DOI: 10.1016/j.molcel.2022.02.027 -
Frontiers in Immunology 2021The thymus provides a microenvironment that supports the generation and selection of T cells. Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial... (Review)
Review
The thymus provides a microenvironment that supports the generation and selection of T cells. Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs) are essential components of the thymic microenvironment and present MHC-associated self-antigens to developing thymocytes for the generation of immunocompetent and self-tolerant T cells. Proteasomes are multicomponent protease complexes that degrade ubiquitinated proteins and produce peptides that are destined to be associated with MHC class I molecules. cTECs specifically express thymoproteasomes that are essential for optimal positive selection of CD8 T cells, whereas mTECs, which contribute to the establishment of self-tolerance in T cells, express immunoproteasomes. Immunoproteasomes are also detectable in dendritic cells and developing thymocytes, additionally contributing to T cell development in the thymus. In this review, we summarize the functions of proteasomes expressed in the thymus, focusing on recent findings pertaining to the functions of the thymoproteasomes and the immunoproteasomes.
Topics: Animals; Antigen Presentation; CD8-Positive T-Lymphocytes; Genetic Variation; Humans; Proteasome Endopeptidase Complex; Thymus Gland
PubMed: 33815406
DOI: 10.3389/fimmu.2021.646209