徳島大学 教育・研究者情報データベース(EDB)

1. 北村 明子

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2. 前川 洋一

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3. 上原 久典([徳島大学.病院.診療科.病理診断科])

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4. 泉 啓介

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5. (英) Kawachi Izumi

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6. (英) Nishizawa Masatoyo

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7. (英) Toyoshima Yasuko

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8. (英) Takahashi Hitoshi

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9. (英) Standley Daron M

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10. (英) Tanaka Keiji

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11. (英) Hamazaki Jun

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12. (英) Murata Shigeo

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13. (英) Obara Koji

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14. (英) Toyoshima Itaru

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15. 安友 康二([徳島大学.大学院医歯薬学研究部.医学域.医科学部門.病理系.生体防御医学])

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(英) A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans.

(英) Proteasomes are multisubunit proteases that play a critical role in maintaining cellular function through the selective degradation of ubiquitinated proteins. When 3 additional subunits, expression of which is induced by IFN-, 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, type 8 (PSMB8), which encodes one of the subunits induced by IFN- 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.

1. (英) Adipocytes
2. (英) Amino Acid Sequence
3. (英) Animals
4. (英) Asian Continental Ancestry Group
5. (英) Cell Differentiation
6. (英) Consanguinity
7. (英) Female
8. (英) Homozygote
9. (英) Humans
10. (英) Inflammation
11. (英) Lipodystrophy
12. (英) Male
13. (英) Mice
14. (英) Models, Molecular
15. (英) Molecular Sequence Data
16. (英) Mutant Proteins
17. (英) Mutation, Missense
18. (英) Pedigree
19. (英) Phenotype
20. (英) Proteasome Endopeptidase Complex
21. (英) RNA, Small Interfering
22. (英) Sequence Homology, Amino Acid

1. (英) Affiliation: Department of Immunology and Parasitology, Institute of Health Biosciences,University of Tokushima Graduate School, Tokushima, Japan.

2. (英) PublicationType: Journal Article

3. (英) PublicationType: Research Support, Non-U.S. Gov't