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Frontiers in Immunology 2023Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical...
Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, and , whereas one patient showed additive loss-of-function mutations in . Variants in two previously not associated proteasome genes, and , were found in a patient who also carried the founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.
Topics: Humans; Proteasome Endopeptidase Complex; Syndrome; Cytoplasm; Dermatitis
PubMed: 37600812
DOI: 10.3389/fimmu.2023.1190104 -
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 -
Cells Jun 2021The ubiquitin-proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential... (Review)
Review
The ubiquitin-proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential functions. The fact that a healthy hematopoietic system relies on the regulation of protein homeostasis and that alterations in the UPS can lead to malignant transformation makes the UPS an attractive therapeutic target for the treatment of hematologic malignancies. Herein, inhibitors of the proteasome, the last and most important component of the UPS enzymatic cascade, have been approved for the treatment of these malignancies. However, their use has been associated with side effects, drug resistance, and relapse. Inhibitors of the immunoproteasome, a proteasomal variant constitutively expressed in the cells of hematopoietic origin, could potentially overcome the encountered problems of non-selective proteasome inhibition. Immunoproteasome inhibitors have demonstrated their efficacy and safety against inflammatory and autoimmune diseases, even though their development for the treatment of hematologic malignancies is still in the early phases. Various immunoproteasome inhibitors have shown promising preliminary results in pre-clinical studies, and one inhibitor is currently being investigated in clinical trials for the treatment of multiple myeloma. Here, we will review data on immunoproteasome function and inhibition in hematopoietic cells and hematologic cancers.
Topics: Hematologic Neoplasms; Hematopoiesis; Humans; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Signal Transduction
PubMed: 34206607
DOI: 10.3390/cells10071577 -
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 -
The Biochemical Journal Sep 2017The ubiquitin proteasome system degrades the great majority of proteins in mammalian cells. Countless studies have described how ubiquitination promotes the selective... (Review)
Review
The ubiquitin proteasome system degrades the great majority of proteins in mammalian cells. Countless studies have described how ubiquitination promotes the selective degradation of different cell proteins. However, there is a small but the growing literature that protein half-lives can also be regulated by post-translational modifications of the 26S proteasome. The present study reviews the ability of several kinases to alter proteasome function through subunit phosphorylation. For example, PKA (protein kinase A) and DYRK2 (dual-specificity tyrosine-regulated kinase 2) stimulate the proteasome's ability to degrade ubiquitinated proteins, peptides, and adenosine triphosphate, while one kinase, ASK1 (apoptosis signal-regulating kinase 1), inhibits proteasome function during apoptosis. Proteasome phosphorylation is likely to be important in regulating protein degradation because it occurs downstream from many hormones and neurotransmitters, in conditions that raise cyclic adenosine monophosphate or cyclic guanosine monophosphate levels, after calcium influx following synaptic depolarization, and during phases of the cell cycle. Beyond its physiological importance, pharmacological manipulation of proteasome phosphorylation has the potential to combat various diseases. Inhibitors of phosphodiesterases by activating PKA or PKG (protein kinase G) can stimulate proteasomal degradation of misfolded proteins that cause neurodegenerative or myocardial diseases and even reduce the associated pathology in mouse models. These observations are promising since in many proteotoxic diseases, aggregation-prone proteins impair proteasome function, and disrupt protein homeostasis. Conversely, preventing subunit phosphorylation by DYRK2 slows cell cycle progression and tumor growth. However, further research is essential to determine how phosphorylation of different subunits by these (or other) kinases alters the properties of this complex molecular machine and thus influence protein degradation rates.
Topics: Animals; Apoptosis; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP-Dependent Protein Kinases; Humans; Neurons; Phosphoric Monoester Hydrolases; Phosphorylation; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Proteins; Proteolysis
PubMed: 28947610
DOI: 10.1042/BCJ20160809 -
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 -
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 -
Acta Biochimica Et Biophysica Sinica Jul 2014The hallmark of prion disease is the accumulation of misfolded protein PrP(Sc), which is toxic to neuronal cells. The proteasome system is responsible for the rapid,... (Review)
Review
The hallmark of prion disease is the accumulation of misfolded protein PrP(Sc), which is toxic to neuronal cells. The proteasome system is responsible for the rapid, precise, and timely degradation of proteins and plays an important role in cellular protein quality control. Increasing evidence indicates impaired activity of proteasomes in prion diseases. Accumulated PrP(Sc) can directly or indirectly affect proteasome activity. Misfolded protein may influence the assembly and activity of 19S regulatory particle, or post-translational modification of 20S proteasome, which may adversely affect the protein degradation activity of proteasomes. In this review, we summarized the recent findings concerning the possible regulation of proteasomes in prion and other neurodegenerative diseases. The proteasome system may enhance its degradation activity by changing its structure, and this activity can also be increased by related chaperones when neuronal cells are subject to stress. When the proteasome system is inhibited, degradation of protein aggregates via autophagy may increase as a compensatory system. It is possible that a balance exists between the proteasome and autophagy in vivo; when one is impaired, the activity of the other may increase to maintain homeostasis. However, more studies are needed to elucidate the relationship between the proteasome system and autophagy.
Topics: Autophagy; Humans; Neurodegenerative Diseases; Prion Diseases; Proteasome Endopeptidase Complex; Ubiquitin
PubMed: 24829398
DOI: 10.1093/abbs/gmu031 -
Biomolecules May 2022Allostery-regulation at distant sites is a key concept in biology. The proteasome exhibits multiple forms of allosteric regulation. This regulatory communication can... (Review)
Review
Allostery-regulation at distant sites is a key concept in biology. The proteasome exhibits multiple forms of allosteric regulation. This regulatory communication can span a distance exceeding 100 Ångstroms and can modulate interactions between the two major proteasome modules: its core particle and regulatory complexes. Allostery can further influence the assembly of the core particle with regulatory particles. In this focused review, known and postulated interactions between these proteasome modules are described. Allostery may explain how cells build and maintain diverse populations of proteasome assemblies and can provide opportunities for therapeutic interventions.
Topics: Allosteric Regulation; Proteasome Endopeptidase Complex
PubMed: 35740889
DOI: 10.3390/biom12060764