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 7

A missense mutation in PSMB8 hyperactivates B cells.

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A missense mutation in PSMB8 hyperactivates B cells. (A) IL6 express...
(A) IL6 expression in skin from a healthy donor and 2-2B, evaluated by real-time PCR. *P < 0.01. (B) Transformed B cells from 1-3PT were transduced with PSMB8 or a control vector. Expression of PSMB8 in healthy control, 1-3PT–EV, and 1-3PT–PSMB8 transformed B cells were evaluated by Western blotting. Expression of IL6 in PMA- and ionomycin-stimulated control, 1-1M, 1-3PT–EV, and 1-3PT–PSMB8 B cells were evaluated by real-time PCR. *P < 0.01. (C) Expression of IL6 in cells after PMA and ionomycin stimulation in the presence of MEK1/2, p38, or JNK inhibitors, evaluated by real-time PCR. **P < 0.05. (D) Expression of total p38 in 1-3PT–EV and 1-3PT–PSMB8 cells, evaluated by Western blot. (E) Phospho-p38 in healthy control, 1-3PT–EV, and 1-3PT–PSMB8 transformed B cells after PMA and ionomycin stimulation. Gray and black histograms denote cells stained with control rabbit IgG and anti–phospho-p38, respectively. Percentages within histograms denote expression of phospho-p38 in PMA- and ionomycin-stimulated cells. All data are representative of 7 experiments.