Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity

Liu, Yin; Ramot, Yuval; Torrelo, Antonio; Paller, Amy S.; Si, Nuo; Babay, Sofia; Kim, Peter W.; Sheikh, Afzal; Lee, Chyi‐Chia Richard; Chen, Yongqing; Vera, Ángel; Zhang, Xue; Goldbach‐Mansky, Raphaela; Zlotogorski, Abraham

doi:10.1002/art.33368

Cited by 365 publications

(361 citation statements)

References 45 publications

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“…Several reports expand the spectrum of the clinical and histological findings with more variables and novel gene mutations; one patient with CANDLE syndrome had no mutations, which probably emphasizes the phenotypic variation and genetic heterogeneity underlying this syndrome. [14][15][16][17] SLE is the prototypical model of autoimmune diseases. It is a complex disease with heterogeneous presentations and chronic unpredictable, relapsingremitting course.…”

Section: Discussionmentioning

confidence: 99%

Monogenic interferonopathies: Phenotypic and genotypic findings of CANDLE syndrome and its overlap with C1q deficient SLE.

et al. 2017

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Objective: To report the clinical and genetic features of the first cases of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome in an Arab population and to compare them with patients of C1q deficient systemic lupus erythematosus (SLE). Materials and Methods:This is a retrospective case series of patients with CANDLE syndrome and C1q deficient SLE seen at a single tertiary hospital. Medical records were reviewed for demographic data, clinical and laboratory features, histopathology and imaging findings, and response to therapeutic intervention. Descriptive data were summarized.

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Section: Discussionmentioning

confidence: 99%

Monogenic interferonopathies: Phenotypic and genotypic findings of CANDLE syndrome and its overlap with C1q deficient SLE.

et al. 2017

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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%

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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“…Interestingly, rather than IL-1, type I interferon-induced gene expression and target proteins are highly induced in this syndrome, perhaps because of accumulation of unfolded protein fragments normally degraded by the proteasome induce an interferon response [35,36] A role for autophagy in regulating IL-1 secretion and IL-1-related autoinflammatory diseases…”

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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Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity

Cited by 365 publications

References 45 publications

Monogenic interferonopathies: Phenotypic and genotypic findings of CANDLE syndrome and its overlap with C1q deficient SLE.

Monogenic interferonopathies: Phenotypic and genotypic findings of CANDLE syndrome and its overlap with C1q deficient SLE.

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

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