PLoS ONE (Jan 2010)

SIRT1 Regulates Thyroid-Stimulating Hormone Release by Enhancing PIP5Kgamma Activity through Deacetylation of Specific Lysine Residues in Mammals.

  • Sayaka Akieda-Asai,
  • Nobuhiro Zaima,
  • Koji Ikegami,
  • Tomoaki Kahyo,
  • Ikuko Yao,
  • Takahiro Hatanaka,
  • Shun-Ichiro Iemura,
  • Rika Sugiyama,
  • Takeaki Yokozeki,
  • Yoshinobu Eishi,
  • Morio Koike,
  • Kyoji Ikeda,
  • Takuya Chiba,
  • Haruyoshi Yamaza,
  • Isao Shimokawa,
  • Si-Young Song,
  • Akira Matsuno,
  • Akiko Mizutani,
  • Motoji Sawabe,
  • Moses V Chao,
  • Masashi Tanaka,
  • Yasunori Kanaho,
  • Tohru Natsume,
  • Haruhiko Sugimura,
  • Yukari Date,
  • Michael W McBurney,
  • Leonard Guarente,
  • Mitsutoshi Setou

DOI
https://doi.org/10.1371/journal.pone.0011755
Journal volume & issue
Vol. 5, no. 7
p. e11755

Abstract

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BACKGROUND: SIRT1, a NAD-dependent deacetylase, has diverse roles in a variety of organs such as regulation of endocrine function and metabolism. However, it remains to be addressed how it regulates hormone release there. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that SIRT1 is abundantly expressed in pituitary thyrotropes and regulates thyroid hormone secretion. Manipulation of SIRT1 level revealed that SIRT1 positively regulated the exocytosis of TSH-containing granules. Using LC/MS-based interactomics, phosphatidylinositol-4-phosphate 5-kinase (PIP5K)gamma was identified as a SIRT1 binding partner and deacetylation substrate. SIRT1 deacetylated two specific lysine residues (K265/K268) in PIP5Kgamma and enhanced PIP5Kgamma enzyme activity. SIRT1-mediated TSH secretion was abolished by PIP5Kgamma knockdown. SIRT1 knockdown decreased the levels of deacetylated PIP5Kgamma, PI(4,5)P(2), and reduced the secretion of TSH from pituitary cells. These results were also observed in SIRT1-knockout mice. CONCLUSIONS/SIGNIFICANCE: Our findings indicated that the control of TSH release by the SIRT1-PIP5Kgamma pathway is important for regulating the metabolism of the whole body.