RRC ID 18513
Author Kitamura A, Maekawa Y, Uehara H, Izumi K, Kawachi I, Nishizawa M, Toyoshima Y, Takahashi H, Standley DM, Tanaka K, Hamazaki J, Murata S, Obara K, Toyoshima I, Yasutomo K.
Title A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans.
Journal J. Clin. Invest.
Abstract Proteasomes are multisubunit proteases that play a critical role in maintaining cellular function through the selective degradation of ubiquitinated proteins. When 3 additional β subunits, expression of which is induced by IFN-γ, are substituted for their constitutively expressed counterparts, the structure is converted to an immunoproteasome. However, the underlying roles of immunoproteasomes in human diseases are poorly understood. Using exome analysis, we found a homozygous missense mutation (G197V) in immunoproteasome subunit, β type 8 (PSMB8), which encodes one of the β subunits induced by IFN-γ in patients from 2 consanguineous families. Patients bearing this mutation suffered from autoinflammatory responses that included recurrent fever and nodular erythema together with lipodystrophy. This mutation increased assembly intermediates of immunoproteasomes, resulting in decreased proteasome function and ubiquitin-coupled protein accumulation in the patient's tissues. In the patient's skin and B cells, IL-6 was highly expressed, and there was reduced expression of PSMB8. Downregulation of PSMB8 inhibited the differentiation of murine and human adipocytes in vitro, and injection of siRNA against Psmb8 in mouse skin reduced adipocyte tissue volume. These findings identify PSMB8 as an essential component and regulator not only of inflammation, but also of adipocyte differentiation, and indicate that immunoproteasomes have pleiotropic functions in maintaining the homeostasis of a variety of cell types.
Volume 121(10)
Pages 4150-60
Published 2011-10
DOI 10.1172/JCI58414
PII 58414
PMID 21881205
PMC PMC3195477
MeSH Adipocytes / enzymology Adipocytes / immunology Adipocytes / pathology Amino Acid Sequence Animals Asian Continental Ancestry Group / genetics Cell Differentiation Consanguinity Female Homozygote Humans Inflammation / enzymology Inflammation / genetics* Inflammation / immunology Inflammation / pathology Lipodystrophy / enzymology Lipodystrophy / genetics* Lipodystrophy / immunology Lipodystrophy / pathology Male Mice Models, Molecular Molecular Sequence Data Mutant Proteins / chemistry Mutant Proteins / genetics Mutant Proteins / physiology Mutation, Missense* Pedigree Phenotype Proteasome Endopeptidase Complex / chemistry Proteasome Endopeptidase Complex / genetics* Proteasome Endopeptidase Complex / physiology Proteasome Inhibitors RNA, Small Interfering / genetics Sequence Homology, Amino Acid
IF 13.251
Times Cited 86
Human and Animal Cells KOP (RCB2148)