PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy Syndrome

Agarwal, Anil K.; Xing, Chao; DeMartino, George N.; Mizrachi, Dario; Hernández, M.D. Jiménez; Sousa, Ana Berta; Villarreal, Laura Martínez de; Santos, Heloísa G. dos; Garg, Abhimanyu

doi:10.1016/j.ajhg.2010.10.031

Cited by 293 publications

(261 citation statements)

References 31 publications

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“…In different mouse models, the treatment with ONX0914 suppressed autoimmune disease like rheumatoid arthritis, diabetes (Muchamuel et al 2009), colitis , systemic lupus erythematosus (Ichikawa et al 2012), and experimental autoimmune encephalomyelitis (Basler et al 2014). Additionally, this is affirmed by reports that in humans, mutations in the gene encoding for β5i are associated with autoinflammatory disease (Agarwal et al 2010;Arima et al 2011;Kitamura et al 2011). Apparently, the latter regulatory functions of immunoproteasomes are not required in the chicken immune system.…”

Section: Discussionmentioning

confidence: 94%

No evidence for immunoproteasomes in chicken lymphoid organs and activated lymphocytes

Erath

Groettrup

2014

Immunogenetics

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The proteasome is the main protein-degrading machine within the cell, producing ligands for MHC class I molecules. It is a cylindrical multicatalytic protease complex, and the catalytic activity is mediated by the three subunits β1, β2, and β5 which possess caspase-, trypsin-, and chymotrypsin-like activities, respectively. By stimulation with interferon (IFN)-γ the replacement of these subunits by β1i, β2i, and β5i is induced leading to formation of immunoproteasomes with altered proteolytic and antigen processing properties. The genes coding for these immunosubunits are restricted to jawed vertebrates but have so far not been found in the genomes of birds, e.g., chicken, turkey, quail, black grouse and zebra finch. However, the chicken genome sequences are not completely assigned; therefore, we investigated the presence of immunoproteasome on protein level. 20S proteasome was purified from the chicken brain, blood, spleen, and bursa of Fabricius, followed by separation via two-dimensional (2D) gel electrophoresis. We analyzed the protein spots derived from the spleen and brain by mass spectrometry and could identify all 14 proteasomal subunits, but there were no differences detectable in the spot patterns. Moreover, we stimulated the chicken spleen cells with phorbol 12-myristate 13-acetate (PMA) and ionomycin aiming at the induction of immunoproteasome, but in spite of the induction of proliferation and IFN-γ, no evidence for immunoproteasome formation in chicken could be obtained. This result was substantiated by the finding that 20S proteasomes isolated from immune and non-immune tissues showed very similar peptidolytic activities. Taken together, our results indicate that chicken lack immunoproteasomes also on protein level.

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Section: Discussionmentioning

confidence: 94%

No evidence for immunoproteasomes in chicken lymphoid organs and activated lymphocytes

Erath

Groettrup

2014

Immunogenetics

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“…51 Application of the PSMB8 selective inhibitor PR-957 in experimental arthritis or colitis could reduce cytokine production and attenuate disease activity. 10,14 On the other hand, the recently described mutations in PSMB8 15,[52][53][54] were all associated with decreased subunit activity and different inflammatory syndromes, suggesting that i-proteasome suppression may cause additional effects depending on dosage and cell type involved. Moreover, influencing antigen processing and presentation through MHC-I may reduce CD8+ T-cell activation but may also increase the risk of tumors, since i-proteasome exerts a fundamental role in tumor rejection 55,56 and of toxicity by accumulating misfolded proteins.…”

Section: Discussionmentioning

confidence: 99%

“…14 Interestingly, mutations causing joint contractures and muscle atrophy were detected in human proteasome subunit PSMB8. 15 On the other hand, elevated levels of circulating proteasomes as well as autoantibodies against several proteasomal subunits have been detected in patients with autoimmune myositis. 16 Based on the existing but so far indirect assumption of an involvement of the i-proteasome in the pathogenesis of DMD, we investigated whether this system is activated and contributes to a perpetuating crosstalk between antigen-presenting cells and T-cells, via i-proteasome generated peptides in mdx mice.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

et al. 2016

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Duchenne muscular dystrophy is an inherited fatal genetic disease characterized by mutations in dystrophin gene, causing membrane fragility leading to myofiber necrosis and inflammatory cell recruitment in dystrophic muscles. The resulting environment enriched in proinflammatory cytokines, like IFN-γ and TNF-α, determines the transformation of myofiber constitutive proteasome into the immunoproteasome, a multisubunit complex involved in the activation of cell-mediate immunity. This event has a fundamental role in producing peptides for antigen presentation by MHC class I, for the immune response and also for cytokine production and T-cell differentiation. Here, we characterized for the first time the presence of T-lymphocytes activated against revertant dystrophin epitopes, in the animal model of Duchenne muscular dystrophy, the mdx mice. Moreover, we specifically blocked i-proteasome subunit LMP7, which was up-regulated in dystrophic skeletal muscles, and we demonstrated the rescue of the dystrophin expression and the amelioration of the dystrophic phenotype. The i-proteasome blocking lowered myofiber MHC class I expression and self-antigen presentation to T cells, thus reducing the specific antidystrophin T cell response, the muscular cell infiltrate, and proinflammatory cytokine production, together with muscle force recovery. We suggest that i-proteasome inhibition should be considered as new promising therapeutic approach for Duchenne muscular dystrophy pathology.

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“…Genetic defects in the proteasome itself have been recently found to cause autoinflammatory disease. Loss of function mutations in PSMB8, which encodes the 5i immunoproteasome subunit, have been associated with a clinical syndrome characterized by systemic inflammation, neutophilic lipodystrophy, and in older patients, cardiac and hematologic abnormalities [32][33][34]. Although the immunoproteasome plays a role in processing peptides for antigen presentation to T cells, most of the abnormalities found in this syndrome are in innate immunity.…”

Section: Autoinflamamatory Diseases Linked To Disorders In Protein MImentioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy Syndrome

Cited by 293 publications

References 31 publications

No evidence for immunoproteasomes in chicken lymphoid organs and activated lymphocytes

No evidence for immunoproteasomes in chicken lymphoid organs and activated lymphocytes

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

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