奥本 寛治

Okumoto Kanji Ph.D

研究内容

ベルオキシソームは過酸化水素の生成を伴う種々の物質の酸化や極長鎖脂肪酸のβ酸化など多様な機能を持つオルガネラです。ヒトではベルオキシソームの形成不全に起因するZellweger症候群などの致死性の先天性代謝異常症が知られています。私は、ベルオキシソーム形成機構の解明と、その形成過程の障害によるヒトベルオキシソーム欠損症の病因解明を目的として研究を進めてきました。

ベルオキシソーム欠損性動物変異細胞の分離、およびそのベルオキシソーム形成不全を回復させる相補遺伝子(ベルオキシソーム形成因子:PEX遺伝子と呼称)の単離を行い、PEX12、PEX10遺伝子がヒトベルオキシソーム欠損症第Ⅲ群、B群の原因遺伝子であることを検出しました。現在では、哺乳動物で上記2遺伝子を含む計14のPEX遺伝子が同定され、既知ヒトベルオキシソーム欠損症全ての原因遺伝子の確定に至っています。これらPEX遺伝子がコードするタンパク質(ベルオキシンと呼称)の多くは、ベルオキシソーム移行シグナル1型(PTS1)を持つベルオキシソームマトリクスタンパク質の輸送に関与していました(図1)。私は特に、細胞質で翻訳されたベルオキシソーム局在性タンパク質がどのようにして輸送されるのか、ユビキチン化修飾による制御を含むその独特な分子メカニズムを明らかにしようとしています(図2)。


発表論文

1: Noguchi M., Okumoto K., and Fujiki Y.: System to quantify the import of peroxisomal matrix proteins by fluorescence intensity. Genes Cells 18, 476-492 (2013)

2: Natsuyama R., Okumoto K., and Fujiki Y.: Pex5p stabilizes Pex14p: a study using a newly isolated pex5 CHO cell mutant, ZPEG101. Biochem. J. 449, 195-207 (2013)

3: New insights into dynamic and functional assembly of the AAA peroxins, Pex1p and Pex6p, and their membrane receptor Pex26p in shuttling of PTS1-receptor Pex5p during peroxisome biogenesis. Biochim. Biophys. Acta.1823, 145-149 (2012)

4: Miyata N., Okumoto K., Mukai S., Noguchi M., and Fujiki Y.: AWP1/ZFAND6 Functions in Pex5 Export by Interacting with Cys-monoubiquitinated Pex5 and Pex6 AAA ATPase. Traffic 13, 163-183 (2012)

5: Okumoto K., Kametani Y., and Fujiki Y.: Two proteases, Tysnd1 and PsLon, cooparatively regulate fatty-acid b-oxidation in peroxisomal matrix. J. Biol. Chem. 286, 44367-44379 (2011)

6: Okumoto K., Misono S., Miyata N., Matsumoto Y., Mukai S, and Fujiki Y.: Cysteine ubiquitination of PTS1 receptor Pex5p regulates Pex5p recycling. Traffic 12, 1067-1083 (2011)

7: Fujiki Y., Okumoto K., Kinoshita K., and Ghaedi K.: Lessons from peroxisome-deficient Chinese hamster ovary (CHO) cell mutants. Biochim. Biophys. Acta. 1763, 1374-1381 (2006).

8: Tanaka A., Okumoto K., and Fujiki Y.: cDNA cloning and characterization of the third isoform in human peroxin Pex11p. Biochem. Biophys. Res. Commun. 300, 819-823(2003)

9: Okumoto K., Abe I., and Fujiki Y.: Molecular anatomy of the peroxin Pex12p: RING finger domain is essential for Pex12p function and interacts with the peroxisome-targeting signal type 1-receptor Pex5p and a RING peroxin, Pex10p. J. Biol. Chem.275, 25700-25710 (2000)

10: Ghaedi K., Tamura S., Okumoto K., Matsuzono Y., and Fujiki Y.: The peroxin Pex3p initiates membrane assembly in peroxisome biogenesis. Mol. Biol. Cell11, 2085-2102 (2000)

11: Fujiki Y., Okumoto K., Otera H., and Tamura S.: Peroxiosme biogenesis and molecular defects in peroxisome assembly disorders. Cell Biochem. Biophys. 32, 155-164 (2000)

12: Ghaedi K., Kawai A., Okumoto K., Tamura S., Shimozawa N., Suzuki Y., Kondo N., and Fujiki Y.: Isolation and characterization of novel peroxisome biogenesis-defective Chinese hamster ovary cell mutants using green fluorescent protein. Exp. Cell Res.248, 489-497 (1999)

13: Shimizu N., Itoh R., Hirono Y., Otera H., Ghaedi K., Tateishi K., Tamura S., Okumoto K., Harano T., Mukai S., and Fujiki Y.: The peroxin Pex14p, cDNA cloning by functional complementation on a Chinese hamster ovary cell mutant, characterization, and functional analysis. J. Biol. Chem. 274, 12593-12604 (1999)

14: Kinoshita N., Ghaedi K., Shimozawa N., Wanders R.J.A., Matsuzono Y., Imanaka T., Okumoto K., Suzuki Y., Kondo N., and Fujiki Y.: Newly identified Chinese hamster ovary cell mutants are defective in biogenesis of peroxisomal membrane vesicles (peroxisomal ghosts), representing a novel complementation group in mammals. J. Biol. Chem. 273, 24122-24130 (1998)

15: Abe I., Okumoto K., Tamura S., and Fujiki Y.: Clofibrate-inducible, 28-kDa peroxisomal integral membrane protein is encoded by PEX11. FEBS Lett. 431, 468-472 (1998)

16: Okumoto K., Itoh R., Shimozawa N., Suzuki Y., Tamura S., Kondo N., and Fujiki Y.: Mutation in PEX10 is the cause of Zellweger peroxisome deficiency syndrome of complementation group B. Hum. Mol. Genet. 7, 1399-1405 (1998)

17: Okumoto K., Shimozawa N., Kawai A., Tamura S., Tsukamoto T., Osumi T., Moser H., Wanders R.J.A., Suzuki Y., Kondo N., and Fujiki Y.: PEX12, the pathogenic gene of group III Zellweger syndrome: cDNA cloning by functional complementation on a CHO cell mutant, patients analysis, and characterization of Pex12p. Mol. Cell. Biol.18, 4324-4336 (1998)

18: Tamura S., Okumoto K., Toyama R., Shimozawa N., Tsukamoto T., Suzuki Y., Osumi T., Kondo N., and Fujiki Y.: Human PEX1 cloned by functional complementation on a CHO cell mutant is responsible for peroxisome-deficient Zellweger syndrome of complementation group I. Proc. Natl. Acad. Sci. USA.95, 4350-4355 (1998)

19: Shimozawa N., Suzuki Y., Zhang Z., Imamura A., Tsukamoto T., Osumi T., Tateishi K., Okumoto K., Fujiki Y., Orii T., Barth P.G., Wanders R.J.A., and Kondo N.: Peroxisome biogenesis disorders: identification of a new complementation group distinct from peroxisome-deficient CHO mutants and not complemented by human PEX13. Biochem. Biophys. Res. Commun. 243, 368-371 (1998)

20: Otera H., Okumoto K., Tateishi K., Ikoma Y., Matsuda E., Nishimura M., Tsukamoto T., Osumi T., Ohashi K., Higuchi O., and Fujiki Y.: Peroxisome targeting signal type 1 (PTS1) receptor is involved in import of both PTS1 and PTS2: studies with PEX5-defective CHO cell mutants. Mol. Cell. Biol. 18, 388-399 (1998)

21: Okumoto K. and Fujiki Y.: PEX12 encodes an integral membrane protein of peroxisomes. Nature Genet. 17, 265-266 (1997)

22: Okumoto K., Bogaki A., Tateishi K., Tsukamoto T., Osumi T., Shimozawa N., Suzuki Y., Orii T., and Fujiki Y.: Isolation and characterization of peroxisome-deficient Chinese hamster ovary cell mutants representing human complementation group III. Exp. Cell Res. 233, 11-20 (1997)

23: Tateishi K., Okumoto K., Shimozawa N., Tsukamoto T., Osumi T., Suzuki Y., Kondo N., Okano I., and Fujiki Y.: Newly identified Chinese hamster ovary cell mutants defective in peroxisome biogenesis represent two novel complementation groups in mammals. Eur. J. Cell Biol.73, 352-359 (1997)

24: Tsukamoto T., Bogaki A., Okumoto K., Tateishi K., Fujiki Y., Shimozawa N., Suzuki Y., Kondo N., and Osumi T.: Isolation of a new peroxisome-deficient CHO cell mutant defective in peroxisome targeting signal-1 receptor. Biochem. Biophys. Res. Commun. 230, 402-406 (1997)