2011年9月
Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- 巻
- 108
- 号
- 36
- 開始ページ
- 14914
- 終了ページ
- 14919
- 記述言語
- 英語
- 掲載種別
- DOI
- 10.1073/pnas.1106015108
- 出版者・発行元
- NATL ACAD SCIENCES
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.
- リンク情報
- ID情報
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- DOI : 10.1073/pnas.1106015108
- ISSN : 0027-8424
- Web of Science ID : WOS:000294543400043