Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production
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Open Access
- 20 October 2015
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 125 (11), 4196-4211
- https://doi.org/10.1172/jci81260
Abstract
Autosomal recessive mutations in proteasome subunit β 8 (PSMB8), which encodes the inducible proteasome subunit β5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes α7), PSMB4 (encodes β7), PSMB9 (encodes β1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production.Keywords
This publication has 47 references indexed in Scilit:
- Ataxia, Dementia, and Hypogonadotropism Caused by Disordered UbiquitinationNew England Journal of Medicine, 2013
- Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2Nature Genetics, 2012
- Immuno- and Constitutive Proteasome Crystal Structures Reveal Differences in Substrate and Inhibitor SpecificityCell, 2012
- A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humansJCI Insight, 2011
- Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneityArthritis & Rheumatism, 2011
- Impairment of Immunoproteasome Function by β5i/LMP7 Subunit Deficiency Results in Severe Enterovirus MyocarditisPLoS Pathogens, 2011
- Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndromeProceedings of the National Academy of Sciences of the United States of America, 2011
- PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy SyndromeAmerican Journal of Human Genetics, 2010
- Autoinflammatory Disease Reloaded: A Clinical PerspectiveCell, 2010
- The proteasome maturation protein POMP facilitates major steps of 20S proteasome formation at the endoplasmic reticulumEMBO Reports, 2007