Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome

被引：233

作者：

Arima, Kazuhiko ^{[1
]}

Kinoshita, Akira ^{[2
]}

Mishima, Hiroyuki ^{[2
]}

Kanazawa, Nobuo ^{[3
]}

Kaneko, Takeumi ^{[4
]}

Mizushima, Tsunehiro ^{[5
]}

Ichinose, Kunihiro ^{[1
]}

Nakamura, Hideki ^{[1
]}

Tsujino, Akira ^{[6
]}

Kawakami, Atsushi ^{[1
]}

Matsunaka, Masahiro ^{[3
]}

Kasagi, Shimpei ^{[7
]}

Kawano, Seiji ^{[7
]}

Kumagai, Shunichi ^{[7
]}

Ohmura, Koichiro ^{[8
]}

Mimori, Tsuneyo ^{[8
]}

Hirano, Makito ^{[9
]}

Ueno, Satoshi ^{[9
]}

Tanaka, Keiko ^{[10
]}

Tanaka, Masami ^{[11
]}

Toyoshima, Itaru ^{[12
,13
]}

Sugino, Hirotoshi ^{[14
]}

Yamakawa, Akio ^{[15
]}

Tanaka, Keiji ^{[16
]}

Niikawa, Norio ^{[17
]}

Furukawa, Fukumi ^{[3
]}

Murata, Shigeo ^{[4
]}

Eguchi, Katsumi ^{[1
]}

Ida, Hiroaki ^{[1
,18
]}

Yoshiura, Koh-ichiro ^{[2
]}

机构：

[1] Nagasaki Univ, Unit Translat Med, Dept Immunol & Rheumatol, Grad Sch Biomed Sci, Nagasaki 8528501, Japan

[2] Nagasaki Univ, Dept Human Genet, Grad Sch Biomed Sci, Nagasaki 8528523, Japan

[3] Wakayama Med Univ, Dept Dermatol, Wakayama 6410012, Japan

[4] Univ Tokyo, Lab Prot Metab, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan

[5] Univ Hyogo, Dept Life Sci, Picobiol Inst, Grad Sch Life Sci, Kamigori, Hyogo 6781297, Japan

[6] Nagasaki Univ, Unit Translat Med, Dept Neurol & Neurosci, Grad Sch Biomed Sci, Nagasaki 8528501, Japan

[7] Kobe Univ, Grad Sch Med, Dept Clin Pathol & Immunol, Kobe, Hyogo 6500017, Japan

[8] Kyoto Univ, Grad Sch Med, Dept Rheumatol & Clin Immunol, Kyoto 6068507, Japan

[9] Nara Med Univ, Dept Neurol, Nara 6348522, Japan

[10] Kanazawa Med Univ, Dept Neurol, Kanazawa, Ishikawa 9200293, Japan

[11] Natl Utano Hosp, Dept Neurol, Ukyo Ku, Kyoto 6168255, Japan

[12] Akita Univ, Sch Med, Dept Neurol, Akita 0108543, Japan

[13] Akita Univ, Sch Med, Med Educ Ctr, Akita 0108543, Japan

[14] Sugino Pediat Clin, Asakita Ku, Hiroshima 7310231, Japan

[15] Univ Tokyo, Off Strateg Management, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan

[16] Tokyo Metropolitan Inst Med Sci, Lab Prot Metab, Setagaya Ku, Tokyo 1568506, Japan

[17] Hlth Sci Univ Hokkaido, Res Inst Personalized Hlth Sci, Ishikari, Hokkaido 0610293, Japan

[18] Kurume Univ, Sch Med, Dept Med, Div Respirol Neurol & Rheumatol, Fukuoka 8300011, Japan

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2011年 / 108卷 / 36期

基金：

日本学术振兴会;

关键词：

MAMMALIAN 20S PROTEASOME; HYPER-GAMMA-GLOBULINEMIA; NF-KAPPA-B; INFLAMMATORY DISEASES; INHIBITOR BORTEZOMIB; KINASE PHOSPHATASES; MUSCULAR-ATROPHY; INTERLEUKIN-6; ACTIVATION; STRESS;

D O I：

10.1073/pnas.1106015108

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：14914 / 14919

页数：6

共 44 条

[1]

PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy Syndrome [J].