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Cells Jul 2023The proteasome is a multi-catalytic protease complex that is involved in protein quality control via three proteolytic activities (i.e., caspase-, trypsin-, and... (Review)
Review
The proteasome is a multi-catalytic protease complex that is involved in protein quality control via three proteolytic activities (i.e., caspase-, trypsin-, and chymotrypsin-like activities). Most cellular proteins are selectively degraded by the proteasome via ubiquitination. Moreover, the ubiquitin-proteasome system is a critical process for maintaining protein homeostasis. Here, we briefly summarize the structure of the proteasome, its regulatory mechanisms, proteins that regulate proteasome activity, and alterations to proteasome activity found in diverse diseases, chemoresistant cells, and cancer stem cells. Finally, we describe potential therapeutic modalities that use the ubiquitin-proteasome system.
Topics: Proteasome Endopeptidase Complex; Proteolysis; Ubiquitination; Ubiquitin; Proteins
PubMed: 37508510
DOI: 10.3390/cells12141846 -
Molecular Metabolism Mar 2022Ferroptosis continues to emerge as a novel modality of cell death with important therapeutic implications for a variety of diseases, most notably cancer and degenerative...
OBJECTIVE
Ferroptosis continues to emerge as a novel modality of cell death with important therapeutic implications for a variety of diseases, most notably cancer and degenerative diseases. While susceptibility, initiation, and execution of ferroptosis have been linked to reprogramming of cellular lipid metabolism, imbalances in iron-redox homeostasis, and aberrant mitochondrial respiration, the detailed mechanisms of ferroptosis are still insufficiently well understood.
METHODS AND RESULTS
Here we show that diminished proteasome function is a new mechanistic feature of ferroptosis. The transcription factor nuclear factor erythroid-2, like-1 (NFE2L1) protects from ferroptosis by sustaining proteasomal activity. In cellular systems, loss of NFE2L1 reduced cellular viability after the induction of both chemically and genetically induced ferroptosis, which was linked to the regulation of proteasomal activity under these conditions. Importantly, this was reproduced in a Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) patient-derived cell line carrying mutated glutathione peroxidase-4 (GPX4), a critical regulator of ferroptosis. Also, reduced proteasomal activity was associated with ferroptosis in Gpx4-deficient mice. In a mouse model for genetic Nfe2l1 deficiency, we observed brown adipose tissue (BAT) involution, hyperubiquitination of ferroptosis regulators, including the GPX4 pathway, and other hallmarks of ferroptosis.
CONCLUSION
Our data highlight the relevance of the NFE2L1-proteasome pathway in ferroptosis. Manipulation of NFE2L1 activity might enhance ferroptosis-inducing cancer therapies as well as protect from aberrant ferroptosis in neurodegeneration, general metabolism, and beyond.
Topics: Animals; Ferroptosis; Homeostasis; Humans; Mice; Mitochondria; NF-E2-Related Factor 1; Phospholipid Hydroperoxide Glutathione Peroxidase; Proteasome Endopeptidase Complex
PubMed: 34999280
DOI: 10.1016/j.molmet.2022.101436 -
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 -
The Journal of Biological Chemistry Jul 2022The ubiquitin-proteasome system fulfills an essential role in regulating protein homeostasis by spatially and temporally controlling proteolysis in an ATP- and... (Review)
Review
The ubiquitin-proteasome system fulfills an essential role in regulating protein homeostasis by spatially and temporally controlling proteolysis in an ATP- and ubiquitin-dependent manner. However, the localization of proteasomes is highly variable under diverse cellular conditions. In yeast, newly synthesized proteasomes are primarily localized to the nucleus during cell proliferation. Yeast proteasomes are transported into the nucleus through the nuclear pore either as immature subcomplexes or as mature enzymes via adapter proteins Sts1 and Blm10, while in mammalian cells, postmitotic uptake of proteasomes into the nucleus is mediated by AKIRIN2, an adapter protein essentially required for nuclear protein degradation. Stressful growth conditions and the reversible halt of proliferation, that is quiescence, are associated with a decline in ATP and the reorganization of proteasome localization. Cellular stress leads to proteasome accumulation in membraneless granules either in the nucleus or in the cytoplasm. In quiescence, yeast proteasomes are sequestered in an ubiquitin-dependent manner into motile and reversible proteasome storage granules in the cytoplasm. In cancer cells, upon amino acid deprivation, heat shock, osmotic stress, oxidative stress, or the inhibition of either proteasome activity or nuclear export, reversible proteasome foci containing polyubiquitinated substrates are formed by liquid-liquid phase separation in the nucleus. In this review, we summarize recent literature revealing new links between nuclear transport, ubiquitin signaling, and the intracellular organization of proteasomes during cellular stress conditions.
Topics: Active Transport, Cell Nucleus; Adenosine Triphosphate; Animals; Cytoplasm; Mammals; Proteasome Endopeptidase Complex; Saccharomyces cerevisiae; Ubiquitin
PubMed: 35636514
DOI: 10.1016/j.jbc.2022.102083 -
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 -
Current Opinion in Structural Biology Apr 2022Ubiquitin is a small eukaryotic protein so named for its cellular abundance and originally recognized for its role as the posttranslational modification (PTM) "tag"... (Review)
Review
Ubiquitin is a small eukaryotic protein so named for its cellular abundance and originally recognized for its role as the posttranslational modification (PTM) "tag" condemning substrates to degradation by the 26S proteasome. Since its discovery in the 1970s, protein ubiquitination has also been identified as a key regulatory feature in dozens of non-degradative cellular processes. This myriad of roles illustrates the versatility of ubiquitin as a PTM; however, understanding the cellular and molecular factors that enable discrimination between degradative versus non-degradative ubiquitination events has been a persistent challenge. Here, we discuss recent advances in uncovering how site-specificity - the exact residue that gets modified - modulates distinct protein fates and cellular outcomes with an emphasis on how ubiquitination site specificity regulates proteasomal degradation. We explore recent advances in structural biology, biophysics, and cell biology that have enabled a broader understanding of the role of ubiquitination in altering the dynamics of the target protein, including implications for the design of targeted protein degradation therapeutics.
Topics: Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Proteins; Proteolysis; Ubiquitin; Ubiquitination
PubMed: 35247748
DOI: 10.1016/j.sbi.2022.102345 -
Molecules (Basel, Switzerland) Aug 2019Loss of proteome fidelity leads to the accumulation of non-native protein aggregates and oxidatively damaged species: hallmarks of an aged cell. These misfolded and... (Review)
Review
Loss of proteome fidelity leads to the accumulation of non-native protein aggregates and oxidatively damaged species: hallmarks of an aged cell. These misfolded and aggregated species are often found, and suggested to be the culpable party, in numerous neurodegenerative diseases including Huntington's, Parkinson's, Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's Diseases (AD). Many strategies for therapeutic intervention in proteotoxic pathologies have been put forth; one of the most promising is bolstering the efficacy of the proteasome to restore normal proteostasis. This strategy is ideal as monomeric precursors and oxidatively damaged proteins, so called "intrinsically disordered proteins" (IDPs), are targeted by the proteasome. This review will provide an overview of disorders in proteins, both intrinsic and acquired, with a focus on susceptibility to proteasomal degradation. We will then examine the proteasome with emphasis on newly published structural data and summarize current known small molecule proteasome activators.
Topics: Animals; Humans; Intrinsically Disordered Proteins; Oxidation-Reduction; Oxidative Stress; Proteasome Endopeptidase Complex; Protein Aggregates; Protein Aggregation, Pathological; Proteostasis; Structure-Activity Relationship
PubMed: 31387243
DOI: 10.3390/molecules24152841 -
Cells Jul 2022REGγ, a proteasome activator belonging to the 11S (otherwise known as REG, PA28, or PSME) proteasome activator family, is widely present in many eukaryotes. By binding... (Review)
Review
REGγ, a proteasome activator belonging to the 11S (otherwise known as REG, PA28, or PSME) proteasome activator family, is widely present in many eukaryotes. By binding to the 20S catalytic core particle, REGγ acts as a molecular sieve to selectively target proteins for degradation in an ATP- and ubiquitin-independent manner. This non-canonical proteasome pathway directly regulates seemingly unrelated cellular processes including cell growth and proliferation, apoptosis, DNA damage response, immune response, and metabolism. By affecting different pathways, REGγ plays a vital role in the regulation of cellular life and death through the maintenance of protein homeostasis. As a promoter of cellular growth and a key regulator of several tumor suppressors, many recent studies have linked REGγ overexpression with tumor formation and suggested the REGγ-proteasome as a potential target of new cancer-drug development. This review will present an overview of the major functions of REGγ as it relates to the regulation of cellular life and death, along with new mechanistic insights into the regulation of REGγ.
Topics: Autoantigens; Cell Cycle; Humans; Neoplasms; Proteasome Endopeptidase Complex; Ubiquitin
PubMed: 35892577
DOI: 10.3390/cells11152281 -
Biomolecules Jan 2021Protein homeostasis, or proteostasis, is crucial for the functioning of a cell, as proteins that are mislocalized, present in excessive amounts, or aberrant due to... (Review)
Review
Protein homeostasis, or proteostasis, is crucial for the functioning of a cell, as proteins that are mislocalized, present in excessive amounts, or aberrant due to misfolding or other type of damage can be harmful. Proteostasis includes attaining the correct protein structure, localization, and the formation of higher order complexes, and well as the appropriate protein concentrations. Consequences of proteostasis imbalance are evident in a range of neurodegenerative diseases characterized by protein misfolding and aggregation, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. To protect the cell from the accumulation of aberrant proteins, a network of protein quality control (PQC) pathways identifies the substrates and direct them towards refolding or elimination via regulated protein degradation. The main pathway for degradation of misfolded proteins is the ubiquitin-proteasome system. PQC pathways have been first described in the cytoplasm and the endoplasmic reticulum, however, accumulating evidence indicates that the nucleus is an important PQC compartment for ubiquitination and proteasomal degradation of not only nuclear, but also cytoplasmic proteins. In this review, we summarize the nuclear ubiquitin-proteasome pathways involved in proteostasis maintenance in yeast, focusing on inner nuclear membrane-associated degradation (INMAD) and San1-mediated protein quality control.
Topics: Animals; Cell Nucleus; Humans; Proteasome Endopeptidase Complex; Protein Folding; Proteolysis; Proteostasis; Ubiquitin
PubMed: 33406777
DOI: 10.3390/biom11010054 -
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