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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 ?5i in patients with NNS. This G201V mutation disrupts the ?-sheet structure, protrudes from the loop that interfaces with the ?4 subunit, and is in close proximity to the catalytic threonine residue. The ?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-? 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.

SUBMITTER: Arima K

PROVIDER: S-EPMC3169106 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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

Arima Kazuhiko K Kinoshita Akira A Mishima Hiroyuki H Kanazawa Nobuo N Kaneko Takeumi T Mizushima Tsunehiro T Ichinose Kunihiro K Nakamura Hideki H Tsujino Akira A Kawakami Atsushi A Matsunaka Masahiro M Kasagi Shimpei S Kawano Seiji S Kumagai Shunichi S Ohmura Koichiro K Mimori Tsuneyo T Hirano Makito M Ueno Satoshi S Tanaka Keiko K Tanaka Masami M Toyoshima Itaru I Sugino Hirotoshi H Yamakawa Akio A Tanaka Keiji K Niikawa Norio N Furukawa Fukumi F Murata Shigeo S Eguchi Katsumi K Ida Hiroaki H Yoshiura Koh-Ichiro K

Proceedings of the National Academy of Sciences of the United States of America 20110818 36

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 catalyti ...[more]

PMID: 21852578

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Project description:Nakajo-Nishimura syndrome is a proteasome-associated autoinflammatory syndrome with a distinct homozygous mutation in the PSMB8 gene encoding an inducible β5i subunit of the immunoproteasome. Although it is considered that immunoproteasome dysfunction causes cellular stress and contributes to the production of inflammatory cytokines and chemokines, its detailed mechanism is still unknown. On the other hand, hereditary autoinflammatory diseases are considered as a good target for the analyses using induced pluripotent stem cells, whose differentiation systems to the innate immune cells such as neutrophils and monocytes have been established. Therefore, to elucidate the pathogenesis of Nakajo-Nishimura syndrome, we attempted in vitro disease modeling using patient-derived induced pluripotent stem cells. For analyses, isogenic control cells in which the responsible mutation was repaired and another pair of healthy embryonic stem cells and isogenic mutant cells in which the same mutation was introduced had also been prepared with genetic engineering. By comparing a pair of isogenic cells with the wild-type and the mutant PSMB8 gene after differentiation into monocytes and immortalization to synchronize their differentiation stages, the reduction of immunoproteasome enzyme activity and increased cytokine and chemokine production in the mutant cells without stimulation or with interferon-γ plus tumor necrosis factor-α stimulation were observed, and therefore, the autoinflammatory phenotype was successfully reproduced. Decreased cytokine production was observed by the addition of antioxidants as well as inhibitors for Janus kinase and p38-mitogen-activated protein kinase. At the same time, the increased production of reactive oxygen species and phosphorylation of both signal transducers and activator of transcription 1 and p38-mitogen-activated protein kinase were detected without stimulation. Notably, an antioxidant specifically decreased the constitutive phosphorylation of signal transducers and activator of transcription 1. These results indicate the usefulness of a disease modeling using pluripotent stem cell-derived cells in clarification of the pathomechanism and discovery of new therapeutic drugs for Nakajo-Nishimura syndrome and related proteasome-associated autoinflammatory syndromes.

Dataset Information

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

Publications

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

Similar Datasets

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