論文 - 詳細
| RRC ID | 18513 |
|---|---|
| 著者 | 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. |
| タイトル | A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. |
| ジャーナル | 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. |
| 巻・号 | 121(10) |
| ページ | 4150-60 |
| 公開日 | 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 |
| 引用数 | 145 |
| WOS 分野 | MEDICINE, RESEARCH & EXPERIMENTAL |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | KOP(RCB2148) |