Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome
Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome
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DOI：
10.1073/pnas.1106015108
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发表时间：
2011-09-06
影响因子：
11.1
通讯作者：
Yoshiura, Koh-ichiro
中科院分区：
文献类型：
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作者：
Arima, Kazuhiko;Kinoshita, Akira;Yoshiura, Koh-ichiro
Nakajo-Nishimura综合征（NNS）是一种以常染色体隐性方式分离的疾病。症状包括周期性发热、皮疹、部分脂肪肌萎缩和关节挛缩。在此，我们报告了NNS患者中编码免疫蛋白酶体β 5i亚基的人蛋白酶体β亚基8基因（PSMB 8）的突变。这种G201 V突变破坏了β-折叠结构，从与β 4亚基交界的环突出，并且非常接近催化苏氨酸残基。β 5i突变体在免疫蛋白酶体生物发生过程中不能有效地掺入，导致蛋白酶体活性降低以及泛素化和氧化蛋白在表达免疫蛋白酶体的细胞内积累。结果，患者血清中白细胞介素（IL）-6和IFN-γ诱导蛋白（IP）-10的水平显著增加。核磷酸化p38和IL-6的分泌在体外和体内的患者细胞中增加，这可能是在这些患者中观察到的炎症反应和周期性发热的原因。这些结果表明，蛋白酶体亚基内的突变是人类疾病的直接原因，并表明蛋白酶体活性降低可引起炎症。
Nakajo-Nishimura syndrome (NNS) is a disorder that segregates in an autosomal recessive fashion. Symptoms include periodic fever, skin rash, partial lipomuscular atrophy, and joint contracture. Here, we report a mutation in the human proteasome subunit beta type 8 gene (PSMB8) that encodes the immunoproteasome subunit beta 5i in patients with NNS. This G201V mutation disrupts the beta-sheet structure, protrudes from the loop that interfaces with the beta 4 subunit, and is in close proximity to the catalytic threonine residue. The beta 5i mutant is not efficiently incorporated during immunoproteasome biogenesis, resulting in reduced proteasome activity and accumulation of ubiquitinated and oxidized proteins within cells expressing immunoproteasomes. As a result, the level of interleukin (IL)-6 and IFN-gamma inducible protein (IP)-10 in patient sera is markedly increased. Nuclear phosphorylated p38 and the secretion of IL-6 are increased in patient cells both in vitro and in vivo, which may account for the inflammatory response and periodic fever observed in these patients. These results show that a mutation within a proteasome subunit is the direct cause of a human disease and suggest that decreased proteasome activity can cause inflammation.