A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans
Akiko Kitamura, Yoichi Maekawa, Hisanori Uehara, Keisuke Izumi, Izumi Kawachi, Masatoyo Nishizawa, Yasuko Toyoshima, Hitoshi Takahashi, Daron M. Standley, Keiji Tanaka, Jun Hamazaki, Shigeo Murata, Koji Obara, Itaru Toyoshima, Koji Yasutomo
Akiko Kitamura, Yoichi Maekawa, Hisanori Uehara, Keisuke Izumi, Izumi Kawachi, Masatoyo Nishizawa, Yasuko Toyoshima, Hitoshi Takahashi, Daron M. Standley, Keiji Tanaka, Jun Hamazaki, Shigeo Murata, Koji Obara, Itaru Toyoshima, Koji Yasutomo
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Research Article Genetics

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

Akiko Kitamura, Yoichi Maekawa, Hisanori Uehara, Keisuke Izumi, Izumi Kawachi, Masatoyo Nishizawa, Yasuko Toyoshima, Hitoshi Takahashi, Daron M. Standley, Keiji Tanaka, Jun Hamazaki, Shigeo Murata, Koji Obara, Itaru Toyoshima, Koji Yasutomo

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Figure 8

A missense mutation in PSMB8 blocks adipocyte differentiation.

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A missense mutation in PSMB8 blocks adipocyte differentiation. (A an...
(A and B) 3T3-L1 cells were transfected with siRNA against PSMB8 or control siRNA. (A) Expression of PSMB8 was evaluated 24 and 48 hours after transfection by Western blotting. (B) Cell viability was tested by trypan blue staining 48 hours after transfection. (C) Induction of adipocytes was evaluated by staining cells with Oil Red 6 days after induction, and Oil Red–positive cells were also quantified. *P < 0.01. (D) Expression of PSMB8 in human preadipocytes was examined by Western blotting. (E) Expression of PSMB8 or β-actin in human preadipocytes transfected with siRNA against PSMB8 or control siRNA (24 hours after transfection) was evaluated by Western blotting and quantified. *P < 0.01. (F) Human preadipocytes were transfected with siRNA against PSMB8 and induced to differentiate into adipocytes; 12 days after transfection, Oil Red–positive cells were evaluated by densitometry. *P < 0.01. (G) siRNA for PSMB8 or control siRNA was subcutaneously injected into the skin of BALB/c mice. The skin was obtained 11 days after the initial siRNA injection, and the section was stained with hematoxylin and eosin. Original magnification, ×10. Scale bars: 100 μm. Moreover, the number of hair follicles in 10,000 μm2 (10 regions) was counted. *P < 0.01. All data are representative of at least 4 experiments.