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PLoS Pathogens Dec 2021Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all... (Review)
Review
Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all 3 kingdoms. Pharmacological inhibition of proteasomes is detrimental to cell viability. Proteasome inhibitor rugs revolutionize the treatment of multiple myeloma. Proteasomes in pathogenic microbes such as Mycobacterium tuberculosis (Mtb), Plasmodium falciparum (Pf), and other parasites and worms have been validated as therapeutic targets. Starting with Mtb proteasome, efforts in developing inhibitors selective for microbial proteasomes have made great progress lately. In this review, we describe the strategies and pharmacophores that have been used in developing proteasome inhibitors with potency and selectivity that spare human proteasomes and highlight the development of clinical proteasome inhibitor candidates for treatment of leishmaniasis and Chagas disease. Finally, we discuss the future challenges and therapeutical potentials of the microbial proteasome inhibitors.
Topics: Animals; Chagas Disease; Humans; Leishmaniasis; Mycobacterium tuberculosis; Plasmodium falciparum; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 34882737
DOI: 10.1371/journal.ppat.1010058 -
International Journal of Molecular... Jun 2021The 26S proteasome is the principal protease for regulated intracellular proteolysis. This multi-subunit complex is also pivotal for clearance of harmful proteins that... (Review)
Review
The 26S proteasome is the principal protease for regulated intracellular proteolysis. This multi-subunit complex is also pivotal for clearance of harmful proteins that are produced throughout the lifetime of eukaryotes. Recent structural and kinetic studies have revealed a multitude of conformational states of the proteasome in substrate-free and substrate-engaged forms. These conformational transitions demonstrate that proteasome is a highly dynamic machinery during substrate processing that can be also controlled by a number of proteasome-associated factors. Essentially, three distinct family of deubiquitinases-USP14, RPN11, and UCH37-are associated with the 19S regulatory particle of human proteasome. USP14 and UCH37 are capable of editing ubiquitin conjugates during the process of their dynamic engagement into the proteasome prior to the catalytic commitment. In contrast, RPN11-mediated deubiquitination is directly coupled to substrate degradation by sensing the proteasome's conformational switch into the commitment steps. Therefore, proteasome-bound deubiquitinases are likely to tailor the degradation events in accordance with substrate processing steps and for dynamic proteolysis outcomes. Recent chemical screening efforts have yielded highly selective small-molecule inhibitors for targeting proteasomal deubiquitinases, such as USP14 and RPN11. USP14 inhibitors, IU1 and its progeny, were found to promote the degradation of a subset of substrates probably by overriding USP14-imposed checkpoint on the proteasome. On the other hand, capzimin, a RPN11 inhibitor, stabilized the proteasome substrates and showed the anti-proliferative effects on cancer cells. It is highly conceivable that these specific inhibitors will aid to dissect the role of each deubiquitinase on the proteasome. Moreover, customized targeting of proteasome-associated deubiquitinases may also provide versatile therapeutic strategies for induced or repressed protein degradation depending on proteolytic demand and cellular context.
Topics: Enzyme Inhibitors; Humans; Neoplasm Proteins; Neoplasms; Proteasome Endopeptidase Complex; Proteolysis; Pyrroles; Pyrrolidines; Ubiquitin Thiolesterase
PubMed: 34207520
DOI: 10.3390/ijms22126213 -
Proceedings of the National Academy of... Apr 2022Meiotic crossover (CO) recombination is tightly regulated by chromosome architecture to ensure faithful chromosome segregation and to reshuffle alleles between parental...
Meiotic crossover (CO) recombination is tightly regulated by chromosome architecture to ensure faithful chromosome segregation and to reshuffle alleles between parental chromosomes for genetic diversity of progeny. However, regulation of the meiotic chromosome loop/axis organization is poorly understood. Here, we identify a molecular pathway for axis length regulation. We show that the cohesin regulator Pds5 can interact with proteasomes. Meiosis-specific depletion of proteasomes and/or Pds5 results in a similarly shortened chromosome axis, suggesting proteasomes and Pds5 regulate axis length in the same pathway. Protein ubiquitination is accumulated in pds5 and proteasome mutants. Moreover, decreased chromosome axis length in these mutants can be largely rescued by decreasing ubiquitin availability and thus decreasing protein ubiquitination. Further investigation reveals that two ubiquitin E3 ligases, SCF (Skp–Cullin–F-box) and Ufd4, are involved in this Pds5–ubiquitin/proteasome pathway to cooperatively control chromosome axis length. These results support the hypothesis that ubiquitination of chromosome proteins results in a shortened chromosome axis, and cohesin–Pds5 recruits proteasomes onto chromosomes to regulate ubiquitination level and thus axis length. These findings reveal an unexpected role of the ubiquitin–proteasome system in meiosis and contribute to our knowledge of how Pds5 regulates meiotic chromosome organization. A conserved regulatory mechanism probably exists in higher eukaryotes.
Topics: Cell Cycle Proteins; Chromosome Segregation; Chromosomes; Meiosis; Proteasome Endopeptidase Complex; Saccharomyces cerevisiae; Ubiquitin
PubMed: 35439061
DOI: 10.1073/pnas.2106902119 -
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 -
Trends in Plant Science Jun 2023Protein homeostasis is epitomized by an equilibrium between protein biosynthesis and degradation: the 'life and death' of proteins. Approximately one-third of newly... (Review)
Review
Protein homeostasis is epitomized by an equilibrium between protein biosynthesis and degradation: the 'life and death' of proteins. Approximately one-third of newly synthesized proteins are degraded. As such, protein turnover is required to maintain cellular integrity and survival. Autophagy and the ubiquitin-proteasome system (UPS) are the two principal degradation pathways in eukaryotes. Both pathways orchestrate many cellular processes during development and upon environmental stimuli. Ubiquitination of degradation targets is used as a 'death' signal by both processes. Recent findings revealed a direct functional link between both pathways. Here, we summarize key findings in the field of protein homeostasis, with an emphasis on the newly revealed crosstalk between both degradation machineries and how it is decided which pathway facilitates target degradation.
Topics: Proteasome Endopeptidase Complex; Proteolysis; Ubiquitin; Ubiquitination; Autophagy
PubMed: 36801193
DOI: 10.1016/j.tplants.2023.01.013 -
Molecular Metabolism Aug 2022Regulation of proteasomal activity is an essential component of cellular proteostasis and function. This is evident in patients with mutations in proteasome subunits and...
OBJECTIVE
Regulation of proteasomal activity is an essential component of cellular proteostasis and function. This is evident in patients with mutations in proteasome subunits and associated regulators, who suffer from proteasome-associated autoinflammatory syndromes (PRAAS). These patients display lipodystrophy and fevers, which may be partly related to adipocyte malfunction and abnormal thermogenesis in adipose tissue. However, the cell-intrinsic pathways that could underlie these symptoms are unclear. Here, we investigate the impact of two proteasome subunits implicated in PRAAS, Psmb4 and Psmb8, on differentiation, function and proteostasis of brown adipocytes.
METHODS
In immortalized mouse brown pre-adipocytes, levels of Psmb4, Psmb8, and downstream effectors genes were downregulated through reverse transfection with siRNA. Adipocytes were differentiated and analyzed with various assays of adipogenesis, lipogenesis, lipolysis, inflammation, and respiration.
RESULTS
Loss of Psmb4, but not Psmb8, disrupted proteostasis and adipogenesis. Proteasome function was reduced upon Psmb4 loss, but partly recovered by the activation of Nuclear factor, erythroid-2, like-1 (Nfe2l1). In addition, cells displayed higher levels of surrogate inflammation and stress markers, including Activating transcription factor-3 (Atf3). Simultaneous silencing of Psmb4 and Atf3 lowered inflammation and restored adipogenesis.
CONCLUSIONS
Our study shows that Psmb4 is required for adipocyte development and function in cultured adipocytes. These results imply that in humans with PSMB4 mutations, PRAAS-associated lipodystrophy is partly caused by disturbed adipogenesis. While we uncover a role for Nfe2l1 in the maintenance of proteostasis under these conditions, Atf3 is a key effector of inflammation and blocking adipogenesis. In conclusion, our work highlights how proteasome dysfunction is sensed and mitigated by the integrated stress response in adipocytes with potential relevance for PRAAS patients and beyond.
Topics: Adipocytes, Brown; Adipogenesis; Animals; Inflammation; Lipodystrophy; Mice; Proteasome Endopeptidase Complex
PubMed: 35636710
DOI: 10.1016/j.molmet.2022.101518 -
Seminars in Cell & Developmental Biology Mar 2024The ubiquitin proteasome system maintains protein homeostasis by regulating the breakdown of misfolded proteins, thereby preventing misfolded protein aggregates. The... (Review)
Review
The ubiquitin proteasome system maintains protein homeostasis by regulating the breakdown of misfolded proteins, thereby preventing misfolded protein aggregates. The efficient elimination is vital for preventing damage to the cell by misfolded proteins, known as proteotoxic stress. Proteotoxic stress can lead to the collapse of protein homeostasis and can alter the function of the ubiquitin proteasome system. Conversely, impairment of the ubiquitin proteasome system can also cause proteotoxic stress and disrupt protein homeostasis. This review examines two impacts of proteotoxic stress, 1) disruptions to ubiquitin homeostasis (ubiquitin stress) and 2) disruptions to proteasome homeostasis (proteasome stress). Here, we provide a mechanistic description of the relationship between proteotoxic stress and the ubiquitin proteasome system. This relationship is illustrated by findings from several protein misfolding diseases, mainly neurodegenerative diseases, as well as from basic biology discoveries from yeast to mammals. In addition, we explore the importance of the ubiquitin proteasome system in endoplasmic reticulum quality control, and how proteotoxic stress at this organelle is alleviated. Finally, we highlight how cells utilize the ubiquitin proteasome system to adapt to proteotoxic stress and how the ubiquitin proteasome system can be genetically and pharmacologically manipulated to maintain protein homeostasis.
Topics: Animals; Ubiquitin; Proteasome Endopeptidase Complex; Proteotoxic Stress; Proteins; Mammals
PubMed: 37734998
DOI: 10.1016/j.semcdb.2023.08.002 -
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