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 |
2011-10-1
|
DOI |
10.1172/JCI58414
|
PII |
58414
|
PMID |
21881205
|
PMC |
PMC3195477
|
MeSH |
Adipocytes / enzymology
Adipocytes / immunology
Adipocytes / pathology
Amino Acid Sequence
Animals
Asians / 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 |
11.864
|
Times Cited |
145
|
WOS Category
|
MEDICINE, RESEARCH & EXPERIMENTAL
|
Resource |
Human and Animal Cells |
KOP(RCB2148) |