Lipid phosphatases identified by screening a mouse phosphatase shRNA library regulate T-cell differentiation and Protein kinase B AKT signaling
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Authors: Guo, Liying; Martens, Craig; Bruno, Daniel; Porcella, Stephen F.; Yamane, Hidehiro; Caucheteux, Stephane M.; Zhu, Jinfang; Paul, William E.
Abstract
Screening a complete mouse phosphatase lentiviral shRNA library using high-throughput sequencing revealed several phosphatases that regulate CD4 T-cell differentiation. We concentrated on two lipid phosphatases, the myotubularin-related protein (MTMR)9 and -7. Silencing MTMR9 by shRNA or siRNA resulted in enhanced T-helper (Th)1 differentiation and increased Th1 protein kinase B (PKB)/AKT phosphorylation while silencing MTMR7 caused increased Th2 and Th17 differentiation and increased AKT phosphorylation in these cells. Irradiated mice reconstituted with MTMR9 shRNA-transduced bone marrow cells had an elevated proportion of T-box transcription factor T-bet expressors among their CD4 T cells. After adoptive transfer of naive cells from such reconstituted mice, immunization resulted in a greater proportion of T-box transcription factor T-bet-expressing cells. Thus, myotubularin-related proteins have a role in controlling in vitro and in vivo Th-cell differentiation, possibly through regulation of phosphatidylinositol [3,4,5]-trisphosphate activity.
Association of variations in the FTO, SCG3 and MTMR9 genes with metabolic syndrome in a Japanese population
JOURNAL OF HUMAN GENETICS
Authors: Hotta, Kikuko; Kitamoto, Takuya; Kitamoto, Aya; Mizusawa, Seiho; Matsuo, Tomoaki; Nakata, Yoshio; Kamohara, Seika; Miyatake, Nobuyuki; Kotani, Kazuaki; Komatsu, Ryoya; Itoh, Naoto; Mineo, Ikuo; Wada, Jun; Yoneda, Masato; Nakajima, Atsushi; Funahashi, Tohru; Miyazaki, Shigeru; Tokunaga, Katsuto; Masuzaki, Hiroaki; Ueno, Takato; Hamaguchi, Kazuyuki; Tanaka, Kiyoji; Yamada, Kentaro; Hanafusa, Toshiaki; Oikawa, Shinichi; Yoshimatsu, Hironobu; Sakata, Toshiie; Matsuzawa, Yuji; Nakao, Kazuwa; Sekine, Akihiro
Abstract
Metabolic syndrome is defined as a cluster of multiple risk factors, including central obesity, dyslipidemia, hypertension and impaired glucose tolerance, that increase cardiovascular disease morbidity and mortality. Genetic factors are important in the development of metabolic syndrome, as are environmental factors. However, the genetic background of metabolic syndrome is not yet fully clarified. There is evidence that obesity and obesity-related phenotypes are associated with variations in several genes, including NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, SH2B1, FTO, MAF, MC4R, KCTD15, SCG3, MTMR9, TFAP2B, MSRA, LYPLAL1, GCKR and FADS1. To investigate the relationship between metabolic syndrome and variations in these genes in the Japanese population, we genotyped 33 single-nucleotide polymorphisms (SNPs) in 19 genes from 1096 patients with metabolic syndrome and 581 control individuals who had no risk factors for metabolic syndrome. Four SNPs in the FTO gene were significantly related to metabolic syndrome: rs9939609 (P=0.00013), rs8050136 (P=0.00011), rs1558902 (P=6.6 x 10(-5)) and rs1421085 (P=7.4 x 10(-5)). rs3764220 in the SCG3 gene (P=0.0010) and rs2293855 in the MTMR9 gene (P=0.0015) were also significantly associated with metabolic syndrome. SNPs in the FTO, SCG3 and MTMR9 genes had no SNP x SNP epistatic effects on metabolic syndrome. Our data suggest that genetic variations in the FTO, SCG3 and MTMR9 genes independently influence the risk of metabolic syndrome. Journal of Human Genetics (2011) 56, 647-651; doi: 10.1038/jhg.2011.74; published online 28 July 2011
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