2. Academic Validation
  3. 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

  • Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14914-9. doi: 10.1073/pnas.1106015108.
Kazuhiko Arima 1,  Akira Kinoshita,  Hiroyuki Mishima,  Nobuo Kanazawa,  Takeumi Kaneko,  Tsunehiro Mizushima,  Kunihiro Ichinose,  Hideki Nakamura,  Akira Tsujino,  Atsushi Kawakami,  Masahiro Matsunaka,  Shimpei Kasagi,  Seiji Kawano,  Shunichi Kumagai,  Koichiro Ohmura,  Tsuneyo Mimori,  Makito Hirano,  Satoshi Ueno,  Keiko Tanaka,  Masami Tanaka,  Itaru Toyoshima,  Hirotoshi Sugino,  Akio Yamakawa,  Keiji Tanaka,  Norio Niikawa,  Fukumi Furukawa,  Shigeo Murata,  Katsumi Eguchi,  Hiroaki Ida,  Koh-Ichiro Yoshiura
Affiliations

Affiliation

  • 1 Unit of Translational Medicine, Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan.
PMID: 21852578 DOI: 10.1073/pnas.1106015108
Abstract

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 β5i in patients with NNS. This G201V mutation disrupts the β-sheet structure, protrudes from the loop that interfaces with the β4 subunit, and is in close proximity to the catalytic threonine residue. The β5i 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-γ 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.

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