Rheumatoid arthritis as a hyper-endoplasmic-reticulum-associated degradation disease.
We introduce Synoviolin as a novel pathogenic factor in rheumatoid arthritis (RA). Experimental studies indicate that this endoplasmic reticulum (ER)-resident E3 ubiquitin ligase has important functions in the ER-associated degradation (ERAD) system, an essential system for ER homeostasis. Overexpression of Synoviolin in mice causes arthropathy with synovial hyperplasia, whereas heterozygous knockdown results in increased apoptosis of synovial cells and resistance to collagen-induced arthritis in mice. On the basis of these experimental data, we propose that excess elimination of unfolded proteins (that is, 'hyper-ERAD') by overexpression of Synoviolin triggers synovial cell overgrowth and hence a worsening of RA. Further analysis of the hyper-ERAD system may permit the complex pathomechanisms of RA to be uncovered.
Yamasaki
Satoshi
S
Department of Genome Science, Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
Yagishita
Naoko
N
Tsuchimochi
Kaneyuki
K
Nishioka
Kusuki
K
Nakajima
Toshihiro
T
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000502:physiology; D018390:Gene Targeting; D006579:Heterozygote; D006706:Homeostasis; D006801:Humans; D006965:Hyperplasia; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D011489:Protein Denaturation; D017510:Protein Folding; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
C482345:SYVN1 protein, human; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases