The transport mechanism of the lactate transporter between Sertoli cells and spermatocytes and the role of seminolipid in it.

• Project/Area Number: 16K08591
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kochi University
• Principal Investigator: Honke Koichi 高知大学, その他部局等, 副学長 (80190263)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 精子形成 / 精母細胞 / セルトリ細胞 / セミノリピド / 乳酸 / MCT4 / ベイシジン / 細胞外小胞 / 乳酸トランスポーター / 発生・分化 / 生体分子 / 糖鎖 / 脂質

Outline of Final Research Achievements

We have elucidated the molecular function of seminolipid, which is the sulfated glycolipid specifically expressed in mammalian testes. Since the testis has the blood-testis barrier, spermatocytes utilize lactate that is produced from glucose in Sertoli cells as the energy source. We found that the lactate transporter on the plasm membrane of spermatocytes is MCT4 and it can function only after it forms assembly with basigin. After the MCT4 gene is transcribed and translated in Sertoli cells, MCT4 proteins are found to be secreted into the extracellular vesicles and transported to spermatocytes. We found that this secretion of the extracellular vesicles from Sertoli cells is stimulated by seminolipid.

Academic Significance and Societal Importance of the Research Achievements

男性不妊の多くは精子形成障害が原因である。哺乳動物の精子形成は精巣中で起こるが、精子形成細胞と支持細胞のセルトリ細胞の相互作用で進行する。精子形成細胞は２回減数分裂を行い、半数体の精子になる。セミノリピドを欠損したマウスは、第一減数分裂の途中で停止し不妊となることから、精子形成に必須の分子であることがわかっているが、その分子メカニズムは不明であった。本研究によってその分子メカニズムが明らかとなった。本研究により、セルトリ細胞と精子形成細胞間のコミュニケーションに細胞外小胞が使われていることが明らかとなった。正常の発生過程においても細胞外小胞の重要性が明確となった。

Research Products

• [Journal Article] Analysis of lipid raft molecules in the living brain slices (2018)
  • Author(s): Kotani N, Nakano T, Ida Y, Ito R, Hashizume M, Yamaguchi A, Seo M, Araki T, Hojo Y, Honke K, Murakoshi T
  • Journal Title: Neurochem Int Volume: 119 Pages: 140-150
  • DOI: 10.1016/j.neuint.2017.08.012
  • Peer Reviewed
• [Journal Article] ASC amino acid transporter 2, defined by enzyme-mediated activation of radical sources, enhances malignancy of GD2-positive small-cell lung cancer. (2018)
  • Author(s): Nobutoshi Esaki, Yuki Ohkawa, Noboru Hashimoto, Yuhsuke Tsuda, Yuhsuke Ohmi, Robiul H. Bhuiyan, Norihiro Kotani, Koichi Honke, Atsushi Enomoto, Masahide Takahashi, Keiko Furukawa, Koichi Furukawa.
  • Journal Title: Cancer sci. Volume: 109 Issue: 1 Pages: 141-153
  • DOI: 10.1111/cas.13448
  • Peer Reviewed / Open Access
• [Journal Article] Biological functions of sulfoglycolipids and the EMARS method for identification of co-clustered molecules in the membrane microdomains. (2018)
  • Author(s): Honke K.
  • Journal Title: J. Biochem. Volume: 163 Issue: 4 Pages: 253-263
  • DOI: 10.1093/jb/mvx078
  • Peer Reviewed
• [Journal Article] 1.Imamaki R. Ogawa K, Kizuka Y, Komi Y, Kojima S, Kotani N, Honke K, Honda T, Taniguchi N, and Kitazume S (2018)
  • Author(s): 1.Imamaki R. Ogawa K, Kizuka Y, Komi Y, Kojima S, Kotani N, Honke K, Honda T, Taniguchi N, and Kitazume S
  • Journal Title: Oncogene Volume: - Issue: 31 Pages: 4287-4299
  • DOI: 10.1038/s41388-018-0271-7
  • Peer Reviewed / Open Access
• [Journal Article] Tumor-dependent secretion of close homolog of L1 results in elevation of its circulating level in mouse model for human lung tumor (2018)
  • Author(s): Kotani Norihiro、Ida Yui、Nakano Takanari、Sato Izumi、Kuwahara Ryusuke、Yamaguchi Arisa、Tomita Masahiro、Honke Koichi、Murakoshi Takayuki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 501 Issue: 4 Pages: 982-987
  • DOI: 10.1016/j.bbrc.2018.05.096
  • Peer Reviewed
• [Journal Article] Sulfatide species with various fatty acid chains in oligodendrocytes at different developmental stages determined by imaging mass spectrometry (2017)
  • Author(s): Yukie Hirahara, Taketoshi Wakabayashi, Tetsuji Mori, Taro Koike, Ikuko Yao, Masayuki Tsuda , Koichi Honke, Hitoshi Gotoh, Katsuhiko Ono, Hisao Yamada.
  • Journal Title: Journal of Neurochemistry Volume: 140 Issue: 3 Pages: 435-450
  • DOI: 10.1111/jnc.13897
  • NAID: 120006778373
  • Peer Reviewed
• [Journal Article] Ganglioside GD3 enhances invasiveness via Yes activation by forming a complex of GD3/PDGFRα/Yes in gliomas (2015)
  • Author(s): Yuki Ohkawa, Hiroyuki Momota, Akira Kato, Noboru Hashimoto, Yuhsuke Tsuda, Norihiro Kotani, Koichi Honke, Akio Suzumura, Keiko Furukawa, Yuhsuke Ohmi, Atsushi Natsume, Toshihiko Wakabayashi and *Furukawa K
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 32 Pages: 16043-16058
  • DOI: 10.1074/jbc.m115.708834
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] ユニークな脂肪酸組成をもつリン脂質分子種がつくる神経細胞膜機能ドメイン (2018)
  • Author(s): 本家孝一
  • Organizer: 2018年生理学研究所研究会「オルガネラ膜ドメインの機能と病態」
  • Invited
• [Presentation] 膜マイクロドメインを視る分子の眼 (2018)
  • Author(s): 本家孝一
  • Organizer: 第31回植物脂質シンポジウム
  • Invited
• [Presentation] EMARS法の膜マイクロドメイン研究への応用 (2018)
  • Author(s): 本家孝一
  • Organizer: 第123回日本解剖学会全国学術集会
  • Invited
• [Presentation] Seminolipidはセルトリ細胞のexosome分泌を促進して精子形成細胞へ乳酸トランスポーターMCT4を送達する。 (2016)
  • Author(s): 山下竜幸、仁尾景子、矢生健一、宮原 馨、津田雅之、小杉智規、門松健治、本家孝一
  • Organizer: 第89回日本生化学会大会、シンポジウム
  • Place of Presentation: 仙台国際センター／東北大学川内北キャンパス（宮城県仙台市）
  • Year and Date: 2016-09-25
  • Invited
• [Presentation] 硫酸化糖脂質セミノリピドはセルトリ細胞のエクソソーム分泌を促進する。 (2016)
  • Author(s): 山下竜幸、仁尾景子、矢生健一、宮原 馨、津田雅之、小杉智規、門松健治、本家孝一
  • Organizer: 第35回日本糖質学会年会
  • Place of Presentation: 高知市文化プラザ かるぽーと（高知県高知市）
  • Year and Date: 2016-09-01
• [Presentation] A sulfated glycolipid, seminolipid and basigin are requied for the functional expression of the lactate transporter in spermatocytes. (2016)
  • Author(s): Honke K, Yamashita T, Kosugi T, Kadomatsu K.
  • Organizer: NOW-JSPS 2016 Symposium “Glycobiology in Health and Disease”
  • Place of Presentation: Leiden, Netherland
  • Year and Date: 2016-04-19
  • Int'l Joint Research / Invited
• [Book] Medical Biochemistry, 5th Ed. (2019)
  • Author(s): Elbe AD, Honke K.
  • Total Pages: 27
  • Publisher: Elsevier