title: Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome.
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.
authors.affiliation: Unit of Translational Medicine, Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Arima
authors.forename: Akira
authors.initials: A
authors.lastname: Kinoshita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mishima
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kanazawa
authors.forename: Takeumi
authors.initials: T
authors.lastname: Kaneko
authors.forename: Tsunehiro
authors.initials: T
authors.lastname: Mizushima
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Ichinose
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Akira
authors.initials: A
authors.lastname: Tsujino
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawakami
authors.forename: Masahiro
authors.initials: M
authors.lastname: Matsunaka
authors.forename: Shimpei
authors.initials: S
authors.lastname: Kasagi
authors.forename: Seiji
authors.initials: S
authors.lastname: Kawano
authors.forename: Shunichi
authors.initials: S
authors.lastname: Kumagai
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ohmura
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
authors.forename: Makito
authors.initials: M
authors.lastname: Hirano
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueno
authors.forename: Keiko
authors.initials: K
authors.lastname: Tanaka
authors.forename: Masami
authors.initials: M
authors.lastname: Tanaka
authors.forename: Itaru
authors.initials: I
authors.lastname: Toyoshima
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Sugino
authors.forename: Akio
authors.initials: A
authors.lastname: Yamakawa
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Norio
authors.initials: N
authors.lastname: Niikawa
authors.forename: Fukumi
authors.initials: F
authors.lastname: Furukawa
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murata
authors.forename: Katsumi
authors.initials: K
authors.lastname: Eguchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ida
authors.forename: Koh-Ichiro
authors.initials: K
authors.lastname: Yoshiura
mesh_terms: D019943:Amino Acid Substitution; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D009133:Muscular Atrophy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D054875:Ubiquitination / Q000235:genetics
chemical_list: D016207:Cytokines; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex