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Molecular Cell Nov 2023While 19S proteasome regulatory particle (RP) inhibition is a promising new avenue for treating bortezomib-resistant myeloma, the anti-tumor impact of inhibiting 19S RP...
While 19S proteasome regulatory particle (RP) inhibition is a promising new avenue for treating bortezomib-resistant myeloma, the anti-tumor impact of inhibiting 19S RP component PSMD14 could not be explained by a selective inhibition of proteasomal activity. Here, we report that PSMD14 interacts with NSD2 on chromatin, independent of 19S RP. Functionally, PSMD14 acts as a histone H2AK119 deubiquitinase, facilitating NSD2-directed H3K36 dimethylation. Integrative genomic and epigenomic analyses revealed the functional coordination of PSMD14 and NSD2 in transcriptional activation of target genes (e.g., RELA) linked to myelomagenesis. Reciprocally, RELA transactivates PSMD14, forming a PSMD14/NSD2-RELA positive feedback loop. Remarkably, PSMD14 inhibitors enhance bortezomib sensitivity and fosters anti-myeloma synergy. PSMD14 expression is elevated in myeloma and inversely correlated with overall survival. Our study uncovers an unappreciated function of PSMD14 as an epigenetic regulator and a myeloma driver, supporting the pursuit of PSMD14 as a therapeutic target to overcome the treatment limitation of myeloma.
Topics: Humans; Histones; Proteasome Endopeptidase Complex; Bortezomib; Multiple Myeloma; Cell Line, Tumor; Deubiquitinating Enzymes; Proteasome Inhibitors; Trans-Activators
PubMed: 37935198
DOI: 10.1016/j.molcel.2023.10.019 -
Molecular Cell Sep 2023The proteasome is responsible for removal of ubiquitinated proteins. Although several aspects of its regulation (e.g., assembly, composition, and post-translational...
The proteasome is responsible for removal of ubiquitinated proteins. Although several aspects of its regulation (e.g., assembly, composition, and post-translational modifications) have been unraveled, studying its adaptive compartmentalization in response to stress is just starting to emerge. We found that following amino acid starvation, the proteasome is translocated from its large nuclear pool to the cytoplasm-a response regulated by newly identified mTOR-agonistic amino acids-Tyr, Trp, and Phe (YWF). YWF relay their signal upstream of mTOR through Sestrin3 by disrupting its interaction with the GATOR2 complex. The triad activates mTOR toward its downstream substrates p62 and transcription factor EB (TFEB), affecting both proteasomal and autophagic activities. Proteasome translocation stimulates cytosolic proteolysis which replenishes amino acids, thus enabling cell survival. In contrast, nuclear sequestration of the proteasome following mTOR activation by YWF inhibits this proteolytic adaptive mechanism, leading to cell death, which establishes this newly identified pathway as a key stress-coping mechanism.
Topics: Proteasome Endopeptidase Complex; Amino Acids, Aromatic; Cell Survival; Amino Acids; TOR Serine-Threonine Kinases
PubMed: 37738964
DOI: 10.1016/j.molcel.2023.08.016 -
Seminars in Immunology Nov 2023Aging leads to a decline in immune cell function, which leaves the organism vulnerable to infections and age-related multimorbidities. One major player of the adaptive... (Review)
Review
Aging leads to a decline in immune cell function, which leaves the organism vulnerable to infections and age-related multimorbidities. One major player of the adaptive immune response are T cells, and recent studies argue for a major role of disturbed proteostasis contributing to reduced function of these cells upon aging. Proteostasis refers to the state of a healthy, balanced proteome in the cell and is influenced by synthesis (translation), maintenance and quality control of proteins, as well as degradation of damaged or unwanted proteins by the proteasome, autophagy, lysosome and cytoplasmic enzymes. This review focuses on molecular processes impacting on proteostasis in T cells, and specifically functional or quantitative changes of each of these upon aging. Importantly, we describe the biological consequences of compromised proteostasis in T cells, which range from impaired T cell activation and function to enhancement of inflamm-aging by aged T cells. Finally, approaches to improve proteostasis and thus rejuvenate aged T cells through pharmacological or physical interventions are discussed.
Topics: Humans; Aged; Proteostasis; T-Cell Senescence; Aging; Proteasome Endopeptidase Complex; Autophagy
PubMed: 37708826
DOI: 10.1016/j.smim.2023.101838 -
Science Advances Dec 2023Protein degradation in eukaryotic cells is mainly carried out by the 26 proteasome, a macromolecular complex not only present in the cytosol and nucleus but also...
Protein degradation in eukaryotic cells is mainly carried out by the 26 proteasome, a macromolecular complex not only present in the cytosol and nucleus but also associated with various membranes. How proteasomes are anchored to the membrane and the biological meaning thereof have been largely unknown in higher organisms. Here, we show that -myristoylation of the Rpt2 subunit is a general mechanism for proteasome-membrane interaction. Loss of this modification in the Rpt2-G2A mutant cells leads to profound changes in the membrane-associated proteome, perturbs the endomembrane system, and undermines critical cellular processes such as cell adhesion, endoplasmic reticulum-associated degradation and membrane protein trafficking. Rpt2 homozygous mutation is embryonic lethal in mice and is sufficient to abolish tumor growth in a nude mice xenograft model. These findings have defined an evolutionarily conserved mechanism for maintaining membrane protein homeostasis and underscored the significance of compartmentalized protein degradation by myristoyl-anchored proteasomes in health and disease.
Topics: Humans; Animals; Mice; Proteasome Endopeptidase Complex; Membrane Proteins; Proteostasis; Endoplasmic Reticulum-Associated Degradation; Mice, Nude; Lipids
PubMed: 38019907
DOI: 10.1126/sciadv.adj4605 -
Nature Aug 2023Human tripartite motif protein 5α (TRIM5α) is a well-characterized restriction factor for some RNA viruses, including HIV; however, reports are limited for DNA...
Human tripartite motif protein 5α (TRIM5α) is a well-characterized restriction factor for some RNA viruses, including HIV; however, reports are limited for DNA viruses. Here we demonstrate that TRIM5α also restricts orthopoxviruses and, via its SPRY domain, binds to the orthopoxvirus capsid protein L3 to diminish virus replication and activate innate immunity. In response, several orthopoxviruses, including vaccinia, rabbitpox, cowpox, monkeypox, camelpox and variola viruses, deploy countermeasures. First, the protein C6 binds to TRIM5 via the RING domain to induce its proteasome-dependent degradation. Second, cyclophilin A (CypA) is recruited via interaction with the capsid protein L3 to virus factories and virions to antagonize TRIM5α; this interaction is prevented by cyclosporine A (CsA) and the non-immunosuppressive derivatives alisporivir and NIM811. Both the proviral effect of CypA and the antiviral effect of CsA are dependent on TRIM5α. CsA, alisporivir and NIM811 have antiviral activity against orthopoxviruses, and because these drugs target a cellular protein, CypA, the emergence of viral drug resistance is difficult. These results warrant testing of CsA derivatives against orthopoxviruses, including monkeypox and variola.
Topics: Humans; Antiviral Agents; Antiviral Restriction Factors; Capsid Proteins; Cell Line; Cyclophilin A; Poxviridae; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Viral Proteins; Proteasome Endopeptidase Complex
PubMed: 37558876
DOI: 10.1038/s41586-023-06401-0 -
Biochimica Et Biophysica Acta. Gene... Dec 2023The ubiquitin proteasomal system (UPS) represents a highly regulated protein degradation pathway essential for maintaining cellular homeostasis. This system plays a... (Review)
Review
The ubiquitin proteasomal system (UPS) represents a highly regulated protein degradation pathway essential for maintaining cellular homeostasis. This system plays a critical role in several cellular processes, which include DNA damage repair, cell cycle checkpoint control, and immune response regulation. Recently, the UPS has emerged as a promising target for cancer therapeutics due to its involvement in oncogenesis and tumor progression. Here we aim to summarize the key aspects of the UPS and its significance in cancer therapeutics. We begin by elucidating the fundamental components of the UPS, highlighting the role of ubiquitin, E1-E3 ligases, and the proteasome in protein degradation. Furthermore, we discuss the intricate process of ubiquitination and proteasomal degradation, emphasizing the specificity and selectivity achieved through various signaling pathways. The dysregulation of the UPS has been implicated in cancer development and progression. Aberrant ubiquitin-mediated degradation of key regulatory proteins, such as tumor suppressors and oncoproteins, can lead to uncontrolled cell proliferation, evasion of apoptosis, and metastasis. We outline the pivotal role of the UPS in modulating crucial oncogenic pathways, including the regulation of cyclins, transcription factors, Replication stress components and DNA damage response. The increasing recognition of the UPS as a target for cancer therapeutics has spurred the development of small molecules, peptides, and proteasome inhibitors with the potential to restore cellular balance and disrupt tumor growth. We provide an overview of current therapeutic strategies aimed at exploiting the UPS, including the use of proteasome inhibitors, deubiquitinating enzyme inhibitors, and novel E3 ligase modulators. We further discuss novel emerging strategies for the development of next-generation drugs that target proteasome inhibitors. Exploiting the UPS for cancer therapeutics offers promising avenues for developing innovative and effective treatment strategies, providing hope for improved patient outcomes in the fight against cancer.
Topics: Humans; Proteasome Inhibitors; Ubiquitination; Ubiquitin-Protein Ligases; Ubiquitin; Proteasome Endopeptidase Complex; Neoplasms
PubMed: 37633647
DOI: 10.1016/j.bbagrm.2023.194979 -
Advanced Biology Dec 2023Protein degradation is a general process to maintain cell homeostasis. The intracellular protein quality control system mainly includes the ubiquitin-proteasome system... (Review)
Review
Protein degradation is a general process to maintain cell homeostasis. The intracellular protein quality control system mainly includes the ubiquitin-proteasome system and the lysosome pathway. Inspired by the physiological process, strategies to degrade specific proteins have developed, which emerge as potent and effective tools in biological research and drug discovery. This review focuses on recent advances in targeted protein degradation techniques, summarizing the principles, advantages, and challenges. Moreover, the potential applications and future direction in biological science and clinics are also discussed.
Topics: Proteolysis; Proteasome Endopeptidase Complex; Ubiquitin; Ubiquitination; Homeostasis
PubMed: 37518856
DOI: 10.1002/adbi.202300083 -
Cancer Letters Jul 2023Multiple myeloma (MM) is an incurable malignancy of plasma cells. Ivermectin is a US Food and Drug Administration-approved drug for antiparasitic use. Here, we showed...
Multiple myeloma (MM) is an incurable malignancy of plasma cells. Ivermectin is a US Food and Drug Administration-approved drug for antiparasitic use. Here, we showed that ivermectin exerted anti-MM effects and significantly synergized with proteasome inhibitors in vitro and in vivo. Ivermectin alone exhibited mild anti-MM activity in vitro. Further investigation suggested that ivermectin inhibited proteasome activity in the nucleus by repressing the nuclear import of proteasome subunits, such as PSMB5-7 and PSMA3-4. Therefore, ivermectin treatment caused the accumulation of ubiquitylated proteins and the activation of the UPR pathway in MM cells. Furthermore, ivermectin treatment caused DNA damage and DNA damage response (DDR) signaling pathway activation in MM cells. Ivermectin and bortezomib exhibited synergized anti-MM activity in vitro. The dual-drug treatment resulted in synergistic inhibition of proteasome activity and increased DNA damage. An in vivo study using a human MM cell line xenograft mouse model showed that ivermectin and bortezomib efficiently repressed MM tumor growth in vivo, while the dual-drug treatment was well tolerated by experimental animals. Overall, our results demonstrated that ivermectin alone or cotreated with bortezomib might be promising in MM treatment.
Topics: Humans; Animals; Mice; Proteasome Inhibitors; Bortezomib; Multiple Myeloma; Proteasome Endopeptidase Complex; Ivermectin; Disease Models, Animal; Cell Line, Tumor; Antineoplastic Agents
PubMed: 37149018
DOI: 10.1016/j.canlet.2023.216218 -
European Journal of Immunology Apr 2024Immunoproteasomes are a special class of proteasomes, which can be induced with IFN-γ in an inflammatory environment. In recent years, it became evident that certain...
Immunoproteasomes are a special class of proteasomes, which can be induced with IFN-γ in an inflammatory environment. In recent years, it became evident that certain immune cell types constitutively express high levels of immunoproteasomes. However, information regarding the basal expression of proteolytically active immunoproteasome subunits in different types of immune cells is still rare. Hence, we quantified standard proteasome subunits (β1c, β2c, β5c) and immunoproteasome subunits (LMP2, MECL-1, LMP7) in the major murine (CD4 T cells, CD8 T cells, CD19 B cells, CD11c dendritic cells, CD49d natural killer cells, Ly-6G neutrophils) and human immune cell (CD4 T cells, CD8 T cells, CD19 B cells, CD1cCD141 myeloid dendritic cells, CD56 natural killer cells, granulocytes) subsets. The different human immune cell types were isolated from peripheral blood and the murine immune cell subsets from spleen. We found that proteasomes of most immune cell subsets mainly consist of immunoproteasome subunits. Our data will serve as a reference and guideline for immunoproteasome expression and imply a special role of immunoproteasomes in immune cells.
Topics: Animals; Mice; Humans; Proteasome Endopeptidase Complex; CD8-Positive T-Lymphocytes
PubMed: 38458995
DOI: 10.1002/eji.202350613 -
Neuromolecular Medicine Dec 2023Parkinson's disease (PD) is a common neurodegenerative disease that is mainly in middle-aged people and elderly people, and the pathogenesis of PD is complex and... (Review)
Review
Parkinson's disease (PD) is a common neurodegenerative disease that is mainly in middle-aged people and elderly people, and the pathogenesis of PD is complex and diverse. The ubiquitin-proteasome system (UPS) is a master regulator of neural development and the maintenance of brain structure and function. Dysfunction of components and substrates of this UPS has been linked to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Moreover, UPS can regulate α-synuclein misfolding and aggregation, mitophagy, neuroinflammation and oxidative stress to affect the development of PD. In the present study, we review the role of several related E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) on the pathogenesis of PD such as Parkin, CHIP, USP8, etc. On this basis, we summarize the connections and differences of different E3 ubiquitin ligases in the pathogenesis, and elaborate on the regulatory progress of different DUBs on the pathogenesis of PD. Therefore, we can better understand their relationships and provide feasible and valuable therapeutic clues for UPS-related PD treatment research.
Topics: Humans; Aged; Middle Aged; Parkinson Disease; Proteasome Endopeptidase Complex; Ubiquitin; Neurodegenerative Diseases; Mitophagy; Ubiquitin-Protein Ligases
PubMed: 37698835
DOI: 10.1007/s12017-023-08755-0