A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans
A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans
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DOI：
10.1172/jci58414
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发表时间：
2011-10-01
影响因子：
15.9
通讯作者：
Yasutomo, Koji
中科院分区：
文献类型：
--
作者：
Kitamura, Akiko;Maekawa, Yoichi;Yasutomo, Koji
蛋白酶体是一种多亚基蛋白酶，通过选择性降解泛素化蛋白质在维持细胞功能中发挥关键作用。当3个额外的β亚基（其表达由IFN-γ诱导）取代其组成型表达的对应物时，该结构转化为免疫蛋白酶体。然而，免疫蛋白酶体在人类疾病中的潜在作用知之甚少。利用外显子组分析，我们发现了一个纯合错义突变（G197 V）免疫蛋白酶体亚基，β 8型（PSMB 8），编码IFN-γ诱导的β亚基之一，在2个近亲家庭的患者。携带这种突变的患者患有自身炎症反应，包括反复发热和结节性红斑以及脂肪营养不良。这种突变增加了免疫蛋白酶体的组装中间体，导致蛋白酶体功能降低和患者组织中泛素偶联蛋白的积累。在患者的皮肤和B细胞中，IL-6高度表达，PSMB 8的表达减少。PSMB 8的下调抑制了体外小鼠和人脂肪细胞的分化，并且在小鼠皮肤中注射针对PSMB 8的siRNA减少了脂肪细胞组织体积。这些发现确定PSMB 8不仅是炎症的重要组分和调节剂，而且是脂肪细胞分化的重要组分和调节剂，并表明免疫蛋白酶体在维持各种细胞类型的稳态方面具有多效性功能。
Proteasomes are multisubunit proteases that play a critical role in maintaining cellular function through the selective degradation of ubiquitinated proteins. When 3 additional beta subunits, expression of which is induced by IFN-gamma, 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, beta type 8 (PSMB8), which encodes one of the beta subunits induced by IFN-gamma 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.