A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus.
Three SUMO (small ubiquitin-related modifier) genes have been identified in humans, which tag proteins to modulate subcellular localization and/or enhance protein stability and activity. We report the identification of a novel intronless SUMO gene, SUMO-4, that encodes a 95-amino acid protein having an 86% amino acid homology with SUMO-2. In contrast to SUMO-2, which is highly expressed in all of the tissues examined, SUMO-4 mRNA was detected mainly in the kidney. A single nucleotide polymorphism was detected in SUMO-4, substituting a highly conserved methionine with a valine residue (M55V). In HepG2 (liver carcinoma) cells transiently transfected with SUMO-4 expression vectors, Met-55 was associated with the elevated levels of activated heat shock factor transcription factors as compared with Val-55, whereas the levels of NF-kappaB were suppressed to an identical degree. The SUMO-4M (Met) variant is associated with type I diabetes mellitus susceptibility in families (p = 4.0 x 10(-4)), suggesting that it may be involved in the pathogenesis of type I diabetes.
Bohren
Kurt M
KM
Molecular Diabetes and Metabolism Section and the Harry B. and Aileen B. Gordon Diabetes Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
Nadkarni
Varsha
V
Song
Jian H
JH
Gabbay
Kenneth H
KH
Owerbach
David
D
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008715:Methionine / Q000235:genetics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D011110:Polymorphism, Genetic / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics* / Q000378:metabolism*; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014633:Valine / Q000235:genetics
D006360:Heat-Shock Proteins; D016328:NF-kappa B; D011994:Recombinant Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D008715:Methionine; D014633:Valine; D008239:Lysine