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PubMed2001

Interaction of Galpha 12 and Galpha 13 with the cytoplasmic domain of cadherin provides a mechanism for beta -catenin release.

The G12 subfamily of heterotrimeric G proteins, comprised of the alpha-subunits Galpha12 and Galpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. In an attempt to elucidate specific roles of this subfamily in cell regulation, we sought to identify molecular targets of Galpha12. Here we show a specific interaction between the G12 subfamily and the cytoplasmic tails of several members of the cadherin family of cell-surface adhesion proteins. Galpha12 or Galpha13 binding causes dissociation of the transcriptional activator beta-catenin from cadherins. Furthermore, in cells lacking the adenomatous polyposis coli protein required for beta-catenin degradation, expression of mutationally activated Galpha12 or Galpha13 causes an increase in beta-catenin-mediated transcriptional activation. These findings provide a potential molecular mechanism for the previously reported cellular transforming ability of the G12 subfamily and reveal a link between heterotrimeric G proteins and cellular processes controlling growth and differentiation.

Adenocarcinoma↗
PubMed2004

Protein modification by SUMO.

Small ubiquitin-related modifier (SUMO) family proteins function by becoming covalently attached to other proteins as post-translational modifications. SUMO modifies many proteins that participate in diverse cellular processes, including transcriptional regulation, nuclear transport, maintenance of genome integrity, and signal transduction. Reversible attachment of SUMO is controlled by an enzyme pathway that is analogous to the ubiquitin pathway. The functional consequences of SUMO attachment vary greatly from substrate to substrate, and in many cases are not understood at the molecular level. Frequently SUMO alters interactions of substrates with other proteins or with DNA, but SUMO can also act by blocking ubiquitin attachment sites. An unusual feature of SUMO modification is that, for most substrates, only a small fraction of the substrate is sumoylated at any given time. This review discusses our current understanding of how SUMO conjugation is controlled, as well as the roles of SUMO in a number of biological processes.

Amino Acid Sequence↗
PubMed2026

Proteome Profiling Reveals NQO2 Activity Contributing to Proteasome Inhibitor Resistance in Multiple Myeloma Cell Lines.

Proteasome inhibitors (PIs) are frontline therapies for multiple myeloma (MM). Although MM patients initially respond to PIs, resistance frequently emerges. While all PIs nominally target the same proteasomal catalytic subunit (PSMB5), the extent to which resistance mechanisms are the same or different among different PIs or between patients is poorly understood. To address this, we performed proteome and phosphoproteome profiling of 12 MM cell line models, comprising four parental lines (AMO-1, ARH77, L363, and RPMI8226) paired with lines that acquired resistance to bortezomib (BTZ) or carfilzomib (CFZ). Over 7000 proteins and up to 10,000 phosphopeptides were identified per cell line, enabling a comprehensive comparative analysis of shared and cell line-specific resistance signatures at the protein level. Data analysis revealed surprisingly few changes in the phosphoproteome but substantial reprogramming of the proteome in most models. Beyond known adaptations such as the overexpression of the PI target PSMB5 and the drug efflux transporter ABCB1, we identified the oxidoreductases NQO1 and NQO2 as significantly upregulated proteins under chronic proteotoxic stress across several models. Pharmacological follow up in PI resistant AMO-1 cells showed that NQO2 inhibition by imatinib fully restored CFZ sensitivity, validating NQO2 as a contributor to resistance formation in this model system.

Humans↗
PubMed2025

Modulation of the tumor microenvironment by the ubiquitin-proteasome system in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with the tumor microenvironment (TME) playing a pivotal role in its progression and therapeutic resistance. The ubiquitin-proteasome system (UPS), a central regulator of intracellular protein degradation, is increasingly recognized for its involvement in cancer pathogenesis, though its specific role in modulating the CRC TME remains to be fully elucidated. This review aims to systematically summarize current evidence on how the UPS influences the immunosuppressive network within the CRC TME and to evaluate its potential as a therapeutic target. METHODS: We conducted a comprehensive literature search in PubMed, Web of Science, and Scopus databases for original research articles and reviews published between January 2010 and August 2025, using keywords including "ubiquitin-proteasome system," "colorectal cancer," "tumor microenvironment,""immune escape,"and "targeted therapy." Studies were selected based on their relevance to UPS-mediated regulatory mechanisms in CRC TME remodeling, immune cell function, and treatment response. RESULTS: Our analysis of preclinical and clinical evidence reveals that the UPS critically regulates immune evasion in CRC through multiple mechanisms: (1) USP14 stabilizes indoleamine 2,3-dioxygenase 1 (IDO1), enhancing tryptophan catabolism and kynurenine accumulation, which suppresses T-cell activity; (2) E3 ligases including SPOP, C-Cbl, KLHL22, and FBW7 modulate PD-L1/PD-1 protein stability via ubiquitination, thereby influencing immune checkpoint signaling; and (3) ZFP91 facilitates K63-linked ubiquitination of PP2Ac, impairing mTORC1-mediated glycolysis in T cells and reinforcing regulatory T-cell immunosuppression. Additionally, the UPS intersects with key oncogenic pathways such as Wnt/β-catenin, NF-κB, and p53, further shaping the immunosuppressive landscape of CRC. CONCLUSIONS: Targeting the UPS represents a promising strategy to reverse immunosuppression and overcome therapy resistance in CRC. The primary advantage of this approach lies in its ability to simultaneously disrupt multiple immunosuppressive pathways within the TME, offering a potential solution to the limitations of single-target therapies. Current approaches include proteasome inhibitors, E3 ligase modulators, and deubiquitinating enzyme inhibitors, with combination regimens-such as UPS inhibitors with immune checkpoint blockade-showing synergistic efficacy in preclinical models. Future efforts should focus on enhancing the selectivity of UPS-targeting agents, minimizing off-target effects, and integrating genomic profiling to guide personalized treatment. While current evidence strongly supports the therapeutic potential of UPS targeting, its establishment as a reliable alternative therapy in the clinic will depend on overcoming these challenges and validating efficacy in human trials. This review underscores the UPS as a central regulator of the CRC TME and provides a rational basis for novel therapeutic development.

Humans↗
PubMed2026

PSMA1, PSMA5, and PSMB2 serve as prognostic biomarkers and are correlated with tumor-infiltrating leukocytes in HCC.

Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related death. Proteasome (PSM) is the main intracellular proteolytic system in higher eukaryotic cells. It has been reported to be involved in the tumor's onset, metabolism, and survival, and it has been recognized as a therapeutic target for many human cancers. The 20S proteasome subunits, specifically proteasome 20S subunit alpha 1 (PSMA1), proteasome 20S subunit alpha 5 (PSMA5), and proteasome 20S subunit beta 2 (PSMB2), are overexpressed in various malignancies, including HCC. Nevertheless, the exact role of these genes in HCC prognosis remains only partially understood. Moreover, a reliable predictive biomarker for HCC is essential for supporting the implementation of personalized therapies. Therefore, this study employed a comprehensive bioinformatics approach, integrating data from cBioPortal, Human Protein Atlas (HPA), Oncomine, STRING Viruses, Kaplan-Meier plotter, and other established high-throughput databases and tools. The current study thoroughly examined the expression levels, methylation, and genomic alterations of PSM and their correlation with tumor-infiltrating leukocytes. PSMA1, PSMA5, and PSMB2 are overexpressed in various cancers, including HCC, and their expression levels are associated with tumor grade and stage. The abundance of these genes is linked to diminished DNA methylation levels and genome alterations. Moreover, there was a significant association between the expression levels of these genes and poor prognosis and immune cell infiltration. In conclusion, this study proposes PSMA1, PSMA5, and PSMB2 as biomarkers for HCC.

Humans↗
PubMed2026

Identification and differential regulation of proteasome β family genes by viral infection and cytokines in grass carp (Ctenopharyngodon idella).

Proteasome β (PSMB) subunits are essential components of the proteasome complex and play important roles in antigen processing and immune regulation. In this study, we identified 14 Psmb genes in grass carp (Ctenopharyngodon idella), including seven constitutive Psmbs (Psmb1-7), three immunoproteasome genes (Psmb8-10), two thymoproteasome-related paralogs (Psmb11a and Psmb11b), and two telelost-specific members (Psmb12 and Psmb13). Comparative genomic analyses showed that grass carp Psmb genes are highly conserved in genomic organization, gene synteny, and predicted β-subunit-like protein structures, supporting the evolutionary conservation of the proteasome β-subunit family in fish. Phylogenetic and syntenic analyses further revealed lineage-specific expansion of immunoproteasome-related Psmb genes in teleost fish, with Psmb12 and Psmb13 likely derived from duplications of Psmb9 and Psmb10, respectively. Tissue expression analysis suggested functional divergence among duplicated Psmb members, as constitutive Psmbs were relatively enriched in the brain, whereas immunoproteasome-related and teleost-specific Psmbs were highly expressed in immune- and mucosa-associated tissues. Moreover, GCRV-I infection rapidly induced Psmb8-10 and Psmb11b expression in CIK cells. IFN-γ induced a broader set of Psmb genes than IFNa, whereas IL-10 selectively suppressed several Psmbs. Together, these findings highlight the evolutionary conservation, expansion, and immune-related diversification of the Psmb family in teleost fish.

Animals↗
PubMed2024

Dysfunction of ATP7B Splicing Variant Caused by Enhanced Interaction With COMMD1 in Wilson Disease.

BACKGROUND & AIMS: The association between Wilson disease and various ATP7B mutations is well-established; however, the molecular mechanism underlying the functional consequence of these mutations, particularly the splicing mutations, remains unclear. This study focused on the ATP7B c.1543+1G>C variant, to reveal a universal pathogenic mechanism of the ATP7B mutants with altered N-terminus. METHODS: The splicing assay and RNA pull-down were performed to explore the mechanism of the aberrant splicing. The ATP7B knockout HuH-7 cell line and Atp7b-/- mice were created, and the functional consequence of the mutant ATP7B were evaluated in vitro and in vivo. RESULTS: The c.1543+1G>C mutation resulted in the skipping of ATP7B exon 3, and the mutant ATP7B showed a loss of trans-Golgi network localization and was degraded via the ubiquitin-proteasome pathway, facilitated by enhanced interactions with COMMD1. Elevated intercellular copper concentration and reduced survival rate were observed in HuH-7 cells expressing mutant ATP7B. Restoration of wild-type ATP7B in Atp7b-/- mice resulted in a substantial improvement in phenotype, whereas mice treated with mutant ATP7B did not demonstrate equivalent benefits. CONCLUSIONS: Our research investigated the pathogenicity and mechanism of ATP7B c.1543+1G>C variant, with particular focus on its enhanced interaction with COMMD1 as a potential universal mechanism contributing to the dysfunction of various ATP7B variants. These findings provide a foundation for the development of innovative therapeutic strategies that target abnormal splicing events in a range of hereditary diseases, including Wilson disease.

Copper-Transporting ATPases↗
PubMed2024

Cilia defects upon loss of WDR4 are linked to proteasomal hyperactivity and ubiquitin shortage.

The WD repeat-containing protein 4 (WDR4) has repeatedly been associated with primary microcephaly, a condition of impaired brain and skull growth. Often, faulty centrosomes cause microcephaly, yet aberrant cilia may also be involved. Here, we show using a combination of approaches in human fibroblasts, zebrafish embryos and patient-derived cells that WDR4 facilitates cilium formation. Molecularly, we associated WDR4 loss-of-function with increased protein synthesis and concomitant upregulation of proteasomal activity, while ubiquitin precursor pools are reduced. Inhibition of proteasomal activity as well as supplementation with free ubiquitin restored normal ciliogenesis. Proteasome inhibition ameliorated microcephaly phenotypes. Thus, we propose that WDR4 loss-of-function impairs head growth and neurogenesis via aberrant cilia formation, initially caused by disturbed protein and ubiquitin homeostasis.

Animals↗
PubMed2026

Quantitative proteomics reveals coordinated changes in the proteome during replicative senescence.

Cellular senescence is a state of irreversible cell cycle arrest triggered by telomere erosion, persistent DNA damage or chronic stress. The accumulation of senescent cells disrupts tissue function and contributes to aging and disease. Here, we employ mass spectrometry-based proteomics to systematically interrogate dynamic proteome changes at multiple levels during the progression of replicative cellular senescence. We demonstrate that proteome changes during senescence occur in a coordinated manner, characterized by widespread protein depletion on chromatin. Moreover, components of the cytoplasmic translation machinery are depleted, while mitochondrial proteins display increased insolubility. Autophagic and proteasome activity is compromised in senescent cells along with remodeling of ubiquitin linkages and depletion of ubiquitin E3 ligases. Comparison of the senescent proteome with different pathophysiological cellular states reveals a distinctive senescent signature shaped by changes in the proteostasis network. Collectively, we provide a resource for the exploration of temporally resolved changes in the senescent proteome.

Cellular Senescence↗
PubMed2026

Molecular architecture and spatial organization of proteasomes in the human sperm nucleus.

Proteasomes are fundamental for protein homeostasis and genome integrity and essential in spermatogenesis and fertilization. However, their presence, composition and role within the sperm nucleus are a subject of debate. Here we use in situ cryo-electron tomography in human sperm cells to elucidate the molecular architecture of nuclear proteasomes, which cluster in DNA-free, nuclear cavities within the sperm nucleus. We show that the main population of proteasomes consists of 20S core particles, with a smaller fraction of 20S capped by PA200 activator. Using single-particle cryo-electron microscopy of purified native human sperm proteasomes, we elucidate the features of the essential testis-specific subunit α4s, reporting the presence of a unique splice variant. We resolve a native peptide in the catalytic β2 subunit, providing insight into the proteolysis mechanism and PA200-mediated enhancement of trypsin activity. We show nuclear enrichment of proteasomes during sperm-cell differentiation in human testis tissue, with 20S and PA200 clustering following meiosis, at the spermatid stage. Our findings shed light on the organization and compositional diversity of nuclear proteasomes in human sperm cells, as well as their catalytic function.

Humans↗
PubMed2025

Nfe2l1 dysfunction alters Parkinson's disease-related gene expression and impairs neuronal differentiation under ubiquitin stress in neuronal differentiated P19 Cells.

Proteostasis is essential for neuronal health, and its disruption is implicated in neurodegenerative diseases such as Parkinson's disease (PD). Nfe2l1, a key regulator of proteostasis and ubiquitination, plays a significant role in neuronal health, yet its molecular functions in neuronal cells remain unclear. Our study investigates the role of Nfe2l1 in RA-induced neuronal differentiation of P19 cells under proteasome inhibition. This condition significantly increased Nfe2l1 expression at both protein and RNA levels in wild-type and differentiated cells. In differentiated cells under proteasome inhibition, RNA sequencing revealed an enrichment of neurodegenerative pathways, particularly those associated with PD. Proteasome inhibition led to the upregulation of several PD-related genes, including Atf6, Camk2d, and Sod1. However, Nfe2l1 knockdown in differentiated cells significantly reduced the expression of these genes, highlighting the role of Nfe2l1 in the regulation of PD-related pathways. Knockdown of Nfe2l1 also decreased Neat1, a long non-coding RNA associated with PD pathology, and downregulated the neuronal marker Map2, indicating impaired neuronal differentiation. Furthermore, Nfe2l1 knockdown increased ubiquitination under proteasome inhibition, emphasizing its role in protein degradation and neuronal homeostasis under stress. These findings highlight Nfe2l1 as a critical regulator in neuronal cells and reveal its potential role in maintaining proteostasis and involvement in neurodegenerative disease mechanisms, such as PD.

Parkinson Disease↗
PubMed2025

Anthracyclines attenuate Nrf1-dependent proteolytic pathways and potentiate proteasome inhibitor cytotoxicity.

Proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib are FDA-approved treatments for multiple myeloma, but resistance frequently limits their effectiveness. The transcription factor Nrf1 (NFE2L1) upregulates proteasome and autophagy genes upon proteasome inhibition, contributing to adaptive resistance. In this study, we identified anthracyclines, including doxorubicin, as suppressors of the Nrf1-driven transcriptional response. Mechanistically, doxorubicin impaired Nrf1 binding to antioxidant response elements (AREs) within promoter regions of target genes without affecting Nrf1 processing or nuclear localization. Importantly, aclarubicin, a non-DNA-damaging anthracycline, also attenuated Nrf1 transcriptional activity, indicating that DNA damage is not required for this inhibition. Doxorubicin cotreatment delayed proteasome recovery after pulse inhibition and partially restored sensitivity to carfilzomib in bortezomib-resistant U266 myeloma cells, consistent with genetic knockout of Nrf1. These findings identify a DNA-damage-independent mechanism by which anthracyclines directly obstruct Nrf1-mediated transcriptional induction. Thus, anthracyclines serve as chemical tools to probe the molecular control of proteostasis and suggest a strategy to mitigate Nrf1-driven adaptive response to proteasome inhibition.

Humans↗
PubMed2024

40S Ribosomal protein S6 kinase integrates daylength perception and growth regulation in Arabidopsis thaliana.

Plant growth occurs via the interconnection of cell growth and proliferation in each organ following specific developmental and environmental cues. Therefore, different photoperiods result in distinct growth patterns due to the integration of light and circadian perception with specific Carbon (C) partitioning strategies. In addition, the TARGET OF RAPAMYCIN (TOR) kinase pathway is an ancestral signaling pathway that integrates nutrient information with translational control and growth regulation. Recent findings in Arabidopsis (Arabidopsis thaliana) have shown a mutual connection between the TOR pathway and the circadian clock. However, the mechanistical network underlying this interaction is mostly unknown. Here, we show that the conserved TOR target, the 40S ribosomal protein S6 kinase (S6K) is under circadian and photoperiod regulation both at the transcriptional and post-translational level. Total S6K (S6K1 and S6K2) and TOR-dependent phosphorylated-S6K protein levels were higher during the light period and decreased at dusk especially under short day conditions. Using chemical and genetic approaches, we found that the diel pattern of S6K accumulation results from 26S proteasome-dependent degradation and is altered in mutants lacking the circadian F-box protein ZEITLUPE (ZTL), further strengthening our hypothesis that S6K could incorporate metabolic signals via TOR, which are also under circadian regulation. Moreover, under short days when C/energy levels are limiting, changes in S6K1 protein levels affected starch, sucrose and glucose accumulation and consequently impacted root and rosette growth responses. In summary, we propose that S6K1 constitutes a missing molecular link where day-length perception, nutrient availability and TOR pathway activity converge to coordinate growth responses with environmental conditions.

Arabidopsis↗
PubMed2026

Virome-wide ubiquitin ligase discovery reveals diverse mechanisms of immune evasion.

Viruses are intracellular parasites that reprogram the host proteome to promote replication and evade immune recognition. We applied a virome-wide library of ~10,000 open reading frames to discover viral ubiquitin ligases, mapping their mechanisms of degradation and host substrates using targeted CRISPR screens and proteomics. These viral effectors could be classified as canonical ligases that mimic host E3s, hijackers that redirect host E3s, and noncanonical ligases that rewire cullin-RING ligase machinery. These diverse strategies of virus-mediated degradation converged on immune-related substrates, including JAK1 and CUL1β-TrCP, underscoring immune evasion as a major driver of viral ubiquitin ligase evolution. Our findings elucidate viral strategies for exploiting the ubiquitin-proteasome system with potential for therapeutic targeting.

Humans↗
PubMed2026

Library-based, multiplexed strategy for mapping protein interaction networks via crosslinking.

BACKGROUND: Protein-protein interactions are fundamental to cellular function, yet resolving their interaction interfaces and dynamic behaviors in native biological contexts remains challenging, particularly for weak or transient interactions. Crosslinking strategies based on noncanonical amino acids offer an effective means to capture such interactions; however, traditional single-site incorporation provides limited coverage and may overlook critical interaction hotspots. RESULTS: By employing a mutagenesis library, multiple interaction partners and cross-linking sites of a target protein can be simultaneously screened in a single experiment, without prior knowledge of its precise structural or functional features, enabling effective and unbiased analysis of its interaction network. In this study, we constructed an amber codon-scanning mutagenesis library of PSMD10, facilitating independent incorporation of the photocrosslinking ncAA p-azido-phenylalanine at multiple distinct residues. This approach allowed us to systematically interrogate and precisely map potential interaction regions across the protein surface. Coupled with crosslinking mass spectrometry, we identified multiple residues involved in intermolecular interactions, as well as previously unreported interaction partners, including T2FA, TBA1C, and ATRIP. CONCLUSIONS: These findings expand our understanding of PSMD10-associated proteasome interactome, demonstrate a multiplexed strategy for in situ mapping of protein interaction interfaces with broad coverage, and offer a valuable platform for developing therapeutics that target protein-protein interactions.

Protein Interaction Mapping↗
PubMed2025

Chromosome duplication causes premature aging via defects in ribosome quality control.

Down syndrome, caused by an extra copy of Chromosome 21, causes lifelong problems. One of the most common phenotypes among people with Down syndrome is premature aging, including early tissue decline, neurodegeneration, and shortened life span. Yet the reasons for premature systemic aging are a mystery and difficult to study in humans. Here we show that chromosome amplification in wild yeast also produces premature aging and shortens life span. Chromosome duplication disrupts nutrient-induced cell-cycle arrest, entry into quiescence, and cellular health during chronological aging, across genetic background and independent of which chromosome is amplified. Using a genomic screen, we discovered that these defects are due in part to aneuploidy-induced dysfunction in Ribosome Quality Control (RQC). We show that aneuploids entering quiescence display aberrant ribosome profiles, accumulate RQC intermediates, and harbor an increased load of protein aggregates compared to euploid cells. Although they maintain proteasome activity, aneuploids also show signs of ubiquitin dysregulation and sequestration into foci. Remarkably, inducing ribosome stalling in euploids produces similar aging phenotypes, while up-regulating limiting RQC subunits or poly-ubiquitin alleviates many of the aneuploid defects. We propose that the increased translational load caused by having too many mRNAs accelerates a decline in translational fidelity, contributing to premature aging.

Ribosomes↗
PubMed2025

Homeobox protein MSX-1 restricts hepatitis B virus by promoting ubiquitin-independent proteasomal degradation of HBx protein.

Hepatitis B virus (HBV) X protein (HBx) is a key factor for regulating viral transcription and replication. We recently characterized homeobox protein MSX-1 (MSX1) as a host restriction factor that inhibits HBV gene expression and genome replication by directly binding to HBV enhancer II/core promoter (EnII/Cp) and suppressing its promoter and enhancer activities. Notably, HBx expression was observed to be repressed more drastically by MSX1 compared to other viral antigens. In this work, we report that in addition to transcriptional repression, MSX1 also post-transcriptionally downregulates HBx protein stability. Mechanistically, MSX1 induces ubiquitin-independent proteasomal degradation of HBx, which is mediated through HBx C-terminal domain. Furthermore, this effect on HBx degradation correlates with MSX1-induced upregulation of DNAJA4 and CRYAB expression. Similar to MSX1, both DNAJA4 and CRYAB promote HBx degradation and repress HBV gene expression and genome replication. In chronic hepatitis B (CHB) patients, immune active phase (IA) is associated with higher intrahepatic expression of MSX1, DNAJA4 and CRYAB, and lower serum HBV markers compared to immune tolerant (IT) phase. Finally, HBV infection is significantly suppressed by MSX1 overexpression in both NTCP-overexpressing cell and humanized liver mouse models. These results demonstrate additional and novel mechanisms of MSX1-mediated repression of HBV, and establish MSX1 as a multi-functional HBV restriction factor with therapeutic potential.

Humans↗