title: A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans.
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.
authors: Department of Immunology and Parasitology, Institute of Health Biosciences,University of Tokushima Graduate School, Tokushima, Japan.
authors: Akiko
authors: A
authors: Kitamura
authors: Yoichi
authors: Y
authors: Maekawa
authors: Hisanori
authors: H
authors: Uehara
authors: Keisuke
authors: K
authors: Izumi
authors: Izumi
authors: I
authors: Kawachi
authors: Masatoyo
authors: M
authors: Nishizawa
authors: Yasuko
authors: Y
authors: Toyoshima
authors: Hitoshi
authors: H
authors: Takahashi
authors: Daron M
authors: DM
authors: Standley
authors: Keiji
authors: K
authors: Tanaka
authors: Jun
authors: J
authors: Hamazaki
authors: Shigeo
authors: S
authors: Murata
authors: Koji
authors: K
authors: Obara
authors: Itaru
authors: I
authors: Toyoshima
authors: Koji
authors: K
authors: Yasutomo
mesh_terms: D017667:Adipocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People / Q000235:genetics; D002454:Cell Differentiation; D003241:Consanguinity; D005260:Female; D006720:Homozygote; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008060:Lipodystrophy / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D050505:Mutant Proteins; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex