RESUMEN

Immunoproteasome is a specialized form of proteasome which plays a crucial role in antigen processing and presentation, and enhances immune responses against malignant cells. This review explores the role of immunoproteasome in the anti-tumor immune responses, including immune surveillance and modulation of the tumor microenvironment, as well as its potential as a target for cancer immunotherapy. Furthermore, we have also discussed the therapeutic potential of immunoproteasome inhibitors, strategies to enhance antigen presentation and combination therapies. The ongoing trials and case studies in urology, melanoma, lung, colorectal, and breast cancers have also been summarized. Finally, the challenges facing clinical translation of immunoproteasome-targeted therapies, such as toxicity and resistance mechanisms, and the future research directions have been addressed. This review underscores the significance of targeting the immunoproteasome in combination with other immunotherapies for solid tumors and its potential broader applications in other diseases.

Asunto(s)

RESUMEN

Embryonic stem cells (ESCs) are remarkable for the high activity level of ubiquitin-proteasome system-the molecular machinery of protein degradation in the cell. Various forms of the proteasome complexes comprising different subunits and interacting regulators are responsible for the substrate selectivity and degradation. Immunoproteasomes are amongst these forms which play an important role in antigen presentation; however, a body of recent evidence suggests their functions in pluripotent stem cells. Previous studies have established three consecutive phases of pluripotency, featured by epiblast cells and their cultured counterparts: naïve, formative, and primed phase. In this work, we report that immunoproteasomes and their chaperone co-regulators are suppressed in the naïve state but are readily upregulated in the formative phase of the pluripotency continuum, featured by epiblast-like cells (EpiLCs). Our data lay ground for the further investigation of the biological functions of immunoproteasome in the regulation of proteostasis during early mammalian development.

Asunto(s)

RESUMEN

OBJECTIVE: Obesity represents a significant global health challenge characterized by chronic low-grade inflammation and metabolic dysregulation. The hypothalamus, a key regulator of energy homeostasis, is particularly susceptible to obesity's deleterious effects. This study investigated the role of the immunoproteasome, a specialized proteasomal complex implicated in inflammation and cellular homeostasis, during metabolic diseases. METHODS: The levels of the immunoproteasome ß5i subunit were analyzed by immunostaining, western blotting, and proteasome activity assay in mice fed with either a high-fat diet (HFD) or a regular diet (CHOW). We also characterized the impact of autophagy inhibition on the levels of the immunoproteasome ß5i subunit and the activation of the AKT pathway. Finally, through confocal microscopy, we analyzed the contribution of ß5i subunit inhibition on mitochondrial function by flow cytometry and mitophagy assay. RESULTS: Using an HFD-fed obese mouse model, we found increased immunoproteasome levels in hypothalamic POMC neurons. Furthermore, we observed that palmitic acid (PA), a major component of saturated fats found in HFD, increased the levels of the ß5i subunit of the immunoproteasome in hypothalamic neuronal cells. Notably, the increase in immunoproteasome expression was associated with decreased autophagy, a critical cellular process in maintaining homeostasis and suppressing inflammation. Functionally, PA disrupted the insulin-glucose axis, leading to reduced AKT phosphorylation and increased intracellular glucose levels in response to insulin due to the upregulation of the immunoproteasome. Mechanistically, we identified that the protein PTEN, a key regulator of insulin signaling, was reduced in an immunoproteasome-dependent manner. To further investigate the potential therapeutic implications of these findings, we used ONX-0914, a specific immunoproteasome inhibitor. We demonstrated that this inhibitor prevents PA-induced insulin-glucose axis imbalance. Given the interplay between mitochondrial dysfunction and metabolic disturbances, we explored the impact of ONX-0914 on mitochondrial function. Notably, ONX-0914 preserved mitochondrial membrane potential and attenuated mitochondrial ROS production in the presence of PA. Moreover, we found that ONX-0914 reduced mitophagy in the presence of PA. CONCLUSIONS: Our findings strongly support the pathogenic involvement of the immunoproteasome in hypothalamic neurons in the context of HFD-induced obesity and metabolic disturbances. Targeting the immunoproteasome highlights a promising therapeutic strategy to mitigate the detrimental effects of obesity on the insulin-glucose axis and cellular homeostasis. This study provides valuable insights into the mechanisms driving obesity-related metabolic diseases and offers potential avenues for developing novel therapeutic interventions.

Asunto(s)

RESUMEN

The ubiquitin/proteasome system (UPS) plays a crucial role in maintaining cellular protein homeostasis. The catalytic activity of proteasome in the UPS is regulated by ß1 (PSMB6), ß2 (PSMB7), and ß5 (PSMB5) subunits. Interferon (IFN)-γ, tumor necrosis factor (TNF)-α, inflammation, and oxidative stress can induce the replacement of ß1, ß2, and ß5 with their respective immuno-subunits ß1i (PSMB9), ß2i (PSMB10), and ß5i (PSMB8), which can be assembled into the immunoproteasome. Compared with the standard proteasome, the immunoproteasome exerts enhanced regulatory effects on immune responses, such as processing and presenting MHC class Ⅰ antigens, production of pro-inflammatory cytokines, and T cell differentiation and proliferation. Abnormal aggregation of immunoproteasomes can cause neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. To explore the function of PSMB9 after bacterial infection, we constructed a lentivirus plasmid overexpressing PSMB9-eGFP-His and transfected the plasmid into HEK293T cells for packaging by using a triple-plasmid system in this study. After screening with puromycin, we obtained a stable human leukemia monocytic THP-1 cell line expressing the fusion protein of PSMB9. Western blotting (WB) and fluorescence microscopy verified the expression of the fusion protein in the stable THP-1 cells. Quantitative PCR (qPCR) was employed to measure the copies of PSMB9-eGFP in THP-1 cells. Immunofluorescence results found that eGFP-His did not affect the subcellular localization of PSMB9. The purification with nickel affinity chromatography confirmed that the fusion protein could be assembled into the 20S immunoproteasome and exhibited cleaving activity for fluorescent peptide substrates. These results indicated that the PSMB9-eGFP fusion gene was integrated into the chromosome, and could be stably expressed in the constructed THP-1 cell line. This cell line can be utilized for the research on subcellular localization, dynamic expression, and activity of PSMB9 in live cells at different infection conditions and disease stages. It also provides a model for the stable cell lines construction of other immunoproteasome subunits PSMB8 and PSMB10.

Asunto(s)

RESUMEN

It is widely acknowledged that the aging process is linked to the accumulation of damaged and misfolded proteins. This phenomenon is accompanied by a decrease in proteasome (c20S) activity, concomitant with an increase in immunoproteasome (i20S) activity. These changes can be attributed, in part, to the chronic neuroinflammation that occurs in brain tissues. Neuroinflammation is a complex process characterized by the activation of immune cells in the central nervous system (CNS) in response to injury, infection, and other pathological stimuli. In certain cases, this immune response becomes chronic, contributing to the pathogenesis of various neurological disorders, including chronic pain, Alzheimer's disease, Parkinson's disease, brain traumatic injury, and others. Microglia, the resident immune cells in the brain, play a crucial role in the neuroinflammatory response. Recent research has highlighted the involvement of i20S in promoting neuroinflammation, increased activity of which may lead to the presentation of self-antigens, triggering an autoimmune response against the CNS, exacerbating inflammation, and contributing to neurodegeneration. Furthermore, since i20S plays a role in breaking down accumulated proteins during inflammation within the cell body, any disruption in its activity could lead to a prolonged state of inflammation and subsequent cell death. Given the pivotal role of i20S in neuroinflammation, targeting this proteasome subtype has emerged as a potential therapeutic approach for managing neuroinflammatory diseases. This review delves into the mechanisms of neuroinflammation and microglia activation, exploring the potential of i20S inhibitors as a promising therapeutic strategy for managing neuroinflammatory disorders.

Asunto(s)

RESUMEN

Research on the markers of autoimmune response in multiple sclerosis (MS) is still of great importance. The aim of our study was the evaluation of plasma 20S constitutive proteasome, 20S immunoproteasome, and cathepsin S concentrations as potential biomarkers of a relapsing-remitting type of MS (RRMS). Surface plasmon resonance imaging (SPRI) biosensors were used for the evaluation of protein concentrations. Plasma 20S constitutive proteasome, 20S immunoproteasome, and cathepsin S concentrations were significantly higher in RRMS patients compared to the control group. All three parameters were characterized by excellent usefulness in differentiating MS patients from healthy individuals (AUC equal to or close to 1.000). The plasma concentration of analyzed parameters was not correlated with severity of disability in the course of RRMS (EDSS value), the number of years from the first MS symptoms, the number of years from MS diagnosis, or the number of relapses within the 24-month observational period. Our study has shown that plasma concentrations of 20S constitutive proteasome, 20S immunoproteasome, and cathepsin S have promising potential in differentiating RRMS patients from healthy individuals. All of the analyzed parameters were found to be independent of the time of MS relapse and the severity of neurological symptoms. Hence, their potential as highly sensitive and independent circulating markers of RRMS suggests a stronger association with immunological activity (inflammatory processes) than with the severity of the disease.

RESUMEN

Microglia are the resident immune cells of the central nervous system (CNS). We and others have shown that the inflammatory response of microglia is partially regulated by the immunoproteasome, an inducible form of the proteasome responsible for the generation of major histocompatibility complex (MHC) class I epitopes. While the role of the proteasome in the adaptive immune system is well established, emerging evidence suggests the immunoproteasome may have discrete functions in the innate immune response. Here, we show that inhibiting the immunoproteasome reduces the IFNγ-dependent induction of complement activator C1q, suppresses phagocytosis, and alters the cytokine expression profile in a microglial cell line and microglia derived from human inducible pluripotent stem cells. Moreover, we show that the immunoproteasome regulates the degradation of IκBα, a modulator of NF-κB signaling. Finally, we demonstrate that NADH prevents induction of the immunoproteasome, representing a potential pathway to suppress immunoproteasome-dependent immune responses.

RESUMEN

The immunoproteasome subunit LMP7 (ß5i)/LMP2 (ß1i) dual blockade has been reported to suppress B cell differentiation and activation, suggesting that the dual inhibition of LMP7/LMP2 is a promising approach for treating autoimmune diseases. In contrast, the inhibition of the constitutive proteasome subunit ß5c correlates with cytotoxicity against non-immune cells. Therefore, LMP7/LMP2 dual inhibitors with high selectivity over ß5c may be desirable for treating autoimmune diseases. In this study, we present the optimization and discovery of α-amido boronic acids using cryo-electron microscopy (cryo-EM). The exploitation of structural differences between the proteasome subunits led to the identification of a highly selective LMP7/LMP2 dual inhibitor 19. Molecular dynamics simulation based on cryo-EM structures of the proteasome subunits complexed with 19 explained the inhibitory activity profile. In mice immunized with 4-hydroxy-3-nitrophenylacetyl conjugated to ovalbumin, results indicate that 19 is orally bioavailable and shows promise as potential treatment for autoimmune diseases.

Asunto(s)

RESUMEN

Introduction: IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the (immuno)proteasome probably plays an important role in IgAN. Methods: We firstly analyzed the association of variants in the UBE2L3 region with susceptibility to IgAN in 3,495 patients and 9,101 controls, and then analyzed the association between lead variant and clinical phenotypes in 1,803 patients with regular follow-up data. The blood mRNA levels of members of the ubiquitin-proteasome system including UBE2L3 were analyzed in peripheral blood mononuclear cells from 53 patients and 28 healthy controls. The associations between UBE2L3 and the expression levels of genes involved in Gd-IgA1 production were also explored. Results: The rs131654 showed the most significant association signal in UBE2L3 region (OR: 1.10, 95% CI: 1.04-1.16, p = 2.29 × 10-3), whose genotypes were also associated with the levels of Gd-IgA1 (p = 0.04). The rs131654 was observed to exert cis-eQTL effects on UBE2L3 in various tissues and cell types, particularly in immune cell types in multiple databases. The UBE2L3, LUBAC, and proteasome subunits were highly expressed in patients compared with healthy controls. High expression levels of UBE2L3 were not only associated with higher proteinuria (r = 0.34, p = 0.01) and lower eGFR (r = -0.28, p = 0.04), but also positively correlated with the gene expression of LUBAC and other proteasome subunits. Additionally, mRNA expression levels of UBE2L3 were also positively correlated with IL-6 and RELA, but negatively correlated with the expression levels of the key enzyme in the process of glycosylation including C1GALT1 and C1GALT1C1. Conclusion: In conclusion, by combined genetic association and differed expression analysis of UBE2L3, our data support a role of genetically conferred dysregulation of the (immuno)proteasome in regulating galactose-deficient IgA1 in the development of IgAN.

RESUMEN

The ubiquitinproteasome system (UPS) is the main mechanism responsible for the intracellular degradation of misfolded or damaged proteins. Under inflammatory conditions, the immunoproteasome, an isoform of the proteasome, can be induced, enhancing the antigen-presenting function of the UPS. Furthermore, the immunoproteasome also serves nonimmune functions, such as maintaining protein homeostasis and regulating signalling pathways, and is involved in the pathophysiological processes of various cardiovascular diseases (CVDs). This review aims to provide a comprehensive summary of the current research on the involvement of the immunoproteasome in cardiovascular diseases, with the ultimate goal of identifying novel strategies for the treatment of these conditions.

Asunto(s)

RESUMEN

Immunoproteasomes are involved in various inflammatory diseases. Upon stimulation, standard constitutive proteasomes are partially replaced by newly formed immunoproteasomes that promote inflammatory responses. How the upregulated immunoproteasomes are cleared to constrain hyper-inflammation is unknown. Recently, our studies showed that the pan-FGFR inhibitor LY2874455 efficiently activates macroautophagy/autophagy in macrophages, leading to the degradation of the immunoproteasomes. Immunoproteasome subunits are ubiquitinated and recognized by the selective autophagy receptor SQSTM1/p62. LY2874455 suppresses inflammation induced by lipopolysaccharide both in vivo and in vitro through autophagic degradation of the immunoproteasomes. In summary, our work uncovers a mechanism of inflammation suppression by autophagy in macrophages.

Asunto(s)

RESUMEN

Excessive secretion of pro-inflammatory cytokines leads to the disruption of intestinal barrier in inflammatory bowel disease (IBD). The inflammatory cytokine tumor necrosis factor alpha (TNFα) induces the assembly of the NLRP3 inflammasome, resulting in the augmented secretion of inflammatory cytokines implicated in the pathogenesis of inflammatory bowel disease (IBD). TNFα has also been known to induce the formation of immunoproteasome (IP), which incorporates immunosubunits LMP2, LMP7, and MECL-1. Inhibition of IP activity using the IP subunit LMP2-specific inhibitor YU102, a peptide epoxyketone, decreased the protein levels of NLRP3 and increased the K48-linked polyubiquitination levels of NLRP3 in TNFα-stimulated intestinal epithelial cells. We observed that inhibition of IP activity caused an increase in the protein level of the ubiquitin E3 ligase, tripartite motif-containing protein 31 (TRIM31). TRIM31 facilitated K48-linked polyubiquitination and proteasomal degradation of NLRP3 with an enhanced interaction between NLRP3 and TRIM31 in intestinal epithelial cells. In addition, IP inhibition using YU102 ameliorated the symptoms of colitis in the model mice inflicted with dextran sodium sulfate (DSS). Administration of YU102 in the DSS-treated colitis model mice caused suppression of the NLRP3 protein levels and accompanied inflammatory cytokine release in the intestinal epithelium. Taken together, we demonstrated that inhibiting IP under inflammatory conditions induces E3 ligase TRIM31-mediated NLRP3 degradation, leading to attenuation of the NLRP3 inflammatory response that triggers disruption of intestinal barrier.

Asunto(s)

RESUMEN

Proper protein degradation is required for cellular protein homeostasis and organ function. Particularly, in post-mitotic cells, such as cardiomyocytes, unbalanced proteolysis due to inflammatory stimuli and oxidative stress contributes to organ dysfunction. To ensure appropriate protein turnover, eukaryotic cells exert two main degradation systems, the ubiquitin-proteasome-system and the autophagy-lysosome-pathway. It has been shown that proteasome activity affects the development of cardiac dysfunction differently, depending on the type of heart failure. Studies analyzing the inducible subtype of the proteasome, the immunoproteasome (i20S), demonstrated that the i20S plays a double role in diseased hearts. While i20S subunits are increased in cardiac hypertrophy, atrial fibrillation and partly in myocarditis, the opposite applies to diabetic cardiomyopathy and ischemia/reperfusion injury. In addition, the i20S appears to play a role in autophagy modulation depending on heart failure phenotype. This review summarizes the current literature on the i20S in different heart failure phenotypes, emphasizing the two faces of i20S in injured hearts. A selection of established i20S inhibitors is introduced and signaling pathways linking the i20S to autophagy are highlighted. Mapping the interplay of the i20S and autophagy in different types of heart failure offers potential approaches for developing treatment strategies against heart failure.

Asunto(s)

RESUMEN

Lactic acid bacteria (LAB) possess the ability to argument T cell activity through functional modification of antigen presenting cells (APCs), such as dendritic cells (DCs) and macrophages. Nevertheless, the precise mechanism underlying LAB-induced enhancement of antigen presentation in APCs remains incompletely understood. To address this question, we investigated the detailed mechanism underlying the enhancement of major histocompatibility complex (MHC) class I-restricted antigen presentation in DCs using a probiotic strain known as Lactococcus lactis subsp. Cremoris C60. We found that Heat-killed-C60 (HK-C60) facilitated the processing and presentation of ovalbumin (OVA) peptide antigen OVA257-264 (SIINFEKL) via H-2Kb in bone marrow-derived dendritic cells (BMDCs), leading to increased generation of effector CD8+ T cells both in vitro and in vivo. We also revealed that HK-C60 stimulation augmented the activity of 20S immunoproteasome (20SI) in BMDCs, thereby enhancing the MHC class I-restricted antigen presentation machinery. Furthermore, we assessed the impact of HK-C60 on CD8+ T cell activation in an OVA-expressing B16-F10 murine melanoma model. Oral administration of HK-C60 significantly attenuated tumor growth compared to control treatment. Enhanced Ag processing and presentation machineries in DCs from both Peyer's Patches (PPs) and lymph nodes (LNs) resulted in an increased tumor antigen specific CD8+ T cells. These findings shed new light on the role of LAB in MHC class-I restricted antigen presentation and activation of CD8+ T cells through functional modification of DCs.

Asunto(s)

RESUMEN

Protein homeostasis is the basis of normal life activities, and the proteasome family plays an extremely important function in this process. The proteasome 20S is a concentric circle structure with two α rings and two ß rings overlapped. The proteasome 20S can perform both ATP-dependent and non-ATP-dependent ubiquitination proteasome degradation by binding to various subunits (such as 19S, 11S, and 200 PA), which is performed by its active subunit ß1, ß2, and ß5. The proteasome can degrade misfolded, excess proteins to maintain homeostasis. At the same time, it can be utilized by tumors to degrade over-proliferate and unwanted proteins to support their growth. Proteasomes can affect the development of tumors from several aspects including tumor signaling pathways such as NF-κB and p53, cell cycle, immune regulation, and drug resistance. Proteasome-encoding genes have been found to be overexpressed in a variety of tumors, providing a potential novel target for cancer therapy. In addition, proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib have been put into clinical application as the first-line treatment of multiple myeloma. More and more studies have shown that it also has different therapeutic effects in other tumors such as hepatocellular carcinoma, non-small cell lung cancer, glioblastoma, and neuroblastoma. However, proteasome inhibitors are not much effective due to their tolerance and singleness in other tumors. Therefore, further studies on their mechanisms of action and drug interactions are needed to investigate their therapeutic potential.

RESUMEN

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 (ß1c, ß2c, ß5c) 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, CD1c+CD141+ 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.

Asunto(s)

RESUMEN

BACKGROUND: Impairment of the ubiquitin-proteasome system (UPS) has been implicated in abnormal protein accumulation in Alzheimer's disease. It remains unclear if genetic variation affects the intrinsic properties of neurons that render some individuals more vulnerable to UPS impairment. METHODS: Induced pluripotent stem cell (iPSC)-derived neurons were generated from over 50 genetically variant and highly characterized participants of cohorts of aging. Proteomic profiling, proteasome activity assays, and Western blotting were employed to examine neurons at baseline and in response to UPS perturbation. RESULTS: Neurons with lower basal UPS activity were more vulnerable to tau accumulation following mild UPS inhibition. Chronic reduction in proteasome activity in human neurons induced compensatory elevation of regulatory proteins involved in proteostasis and several proteasome subunits. DISCUSSION: These findings reveal that genetic variation influences basal UPS activity in human neurons and differentially sensitizes them to external factors perturbing the UPS, leading to the accumulation of aggregation-prone proteins such as tau. HIGHLIGHTS: Polygenic risk score for AD is associated with the ubiquitin-proteasome system (UPS) in neurons. Basal proteasome activity correlates with aggregation-prone protein levels in neurons. Genetic variation affects the response to proteasome inhibition in neurons. Neuronal proteasome perturbation induces an elevation in specific proteins involved in proteostasis. Low basal proteasome activity leads to enhanced tau accumulation with UPS challenge.

Asunto(s)

RESUMEN

Mutations in proteasome ß-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome ß2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash. Remaining T cells had limited T cell receptor repertoires, a skewed memory phenotype, and an elevated CD4/CD8 ratio. Bone marrow examination indicated severely impaired B cell maturation with limited V(D)J recombination. All infants received an allogeneic stem cell transplant and exhibited a variety of severe inflammatory complications thereafter, with 2 peri-transplant and 2 delayed deaths. The single long-term transplant survivor showed evidence for genetic rescue through revertant mosaicism overlapping the affected PSMB10 locus. The identified variants (c.166G>C [p.Asp56His] and c.601G>A/c.601G>C [p.Gly201Arg]) were predicted in silico to profoundly disrupt 20S immunoproteasome structure through impaired ß-ring/ß-ring interaction. Our identification of PSMB10 mutations as a cause of SCID-Omenn syndrome reinforces the connection between PRAAS-related diseases and SCID.

Asunto(s)

RESUMEN

Pancreatic cancer is a lethal disease, harboring a five-year overall survival rate of only 13%. Current treatment approaches thus require modulation, with attention shifting towards liberating the stalled efficacy of immunotherapies. Select chemotherapy drugs which possess inherent immune-modifying behaviors could revitalize immune activity against pancreatic tumors and potentiate immunotherapeutic success. In this study, we characterized the influence of gemcitabine, a chemotherapy drug approved for the treatment of pancreatic cancer, on tumor antigen presentation by human leukocyte antigen class I (HLA-I). Gemcitabine increased pancreatic cancer cells' HLA-I mRNA transcripts, total protein, surface expression, and surface stability. Temperature-dependent assay results indicated that the increased HLA-I stability may be due to reduced binding of low affinity peptides. Mass spectrometry analysis confirmed changes in the HLA-I-presented peptide pool post-treatment, and computational predictions suggested improved affinity and immunogenicity of peptides displayed solely by gemcitabine-treated cells. Most of the gemcitabine-exclusive peptides were derived from unique source proteins, with a notable overrepresentation of translation-related proteins. Gemcitabine also increased expression of select immunoproteasome subunits, providing a plausible mechanism for its modulation of the HLA-I-bound peptidome. Our work supports continued investigation of immunotherapies, including peptide-based vaccines, to be used with gemcitabine as new combination treatment modalities for pancreatic cancer.

Asunto(s)

RESUMEN

The immunoproteasome is a central protease complex required for optimal antigen presentation. Immunoproteasome activity is also associated with facilitating the degradation of misfolded and oxidized proteins, which prevents cellular stress. While extensively studied during diseases with increasing evidence suggesting a role for the immunoproteasome during pathological conditions including neurodegenerative diseases, this enzyme complex is believed to be mainly not expressed in the healthy brain. In this study, we show an age-dependent increase in polyubiquitination in the brains of wild-type mice, accompanied by an induction of immunoproteasomes, which was most prominent in neurons and microglia. In contrast, mice completely lacking immunoproteasomes (triple-knockout mice), displayed a strong increase in polyubiquitinated proteins already in the young brain and developed spontaneous epileptic seizures, beginning at the age of 6 months. Injections of kainic acid led to high epilepsy-related mortality of aged triple-knockout mice, confirming increased pathological hyperexcitability states. Notably, the expression of the immunoproteasome was reduced in the brains of patients suffering from epilepsy. In addition, the aged triple-knockout mice showed increased anxiety, tau hyperphosphorylation and degeneration of Purkinje cell population with the resulting ataxic symptoms and locomotion alterations. Collectively, our study suggests a critical role for the immunoproteasome in the maintenance of a healthy brain during ageing.