SIRT1 Regulates Thyroid-Stimulating Hormone Release by Enhancing PIP5Kγ[subscript gamma] Activity through Deacetylation of Specific Lysine Residues in Mammals

SIRT1 Regulates Thyroid-Stimulating Hormone Release by Enhancing PIP5Kγ[subscript gamma] Activity through Deacetylation of Specific Lysine Residues in Mammals

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 ex...

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Bibliographic Details
Main Authors: Guarente, Leonard Pershing, Akieda-Asai, Sayaka, Zaima, Nobuhiro, Ikegami, Koji, Kahyo, Tomoaki, Yao, Ikuko, Hatanaka, Takahiro, Iemura, Shun-ichiro, Sugiyama, Rika, Yokozeki, Takeaki, Eishi, Yoshinobu, Koike, Morio, Ikeda, Kyoji, Chiba, Takuya, Yamaza, Haruyoshi, Shimokawa, Isao, Song, Si-Young, Matsuno, Akira, Mizutani, Akiko, Sawabe, Motoji, Chao, Moses V., Tanaka, Masashi, Kanaho, Yasunori, Natsume, Tohru, Sugimura, Haruhiko, Date, Yukari, McBurney, Michael W., Setou, Mitsutoshi
Other Authors: Massachusetts Institute of Technology. Department of Biology
Format: Article
Language:en_US
Published: Public Library of Science 2010
Online Access:http://hdl.handle.net/1721.1/60353
https://orcid.org/0000-0003-4064-2510
Description
Summary: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)γ[subscript gamma] was identified as a SIRT1 binding partner and deacetylation substrate. SIRT1 deacetylated two specific lysine residues (K265/K268) in PIP5Kγ[subscript gamma] and enhanced PIP5Kγ[subscript gamma] enzyme activity. SIRT1-mediated TSH secretion was abolished by PIP5Kγ[subscript gamma] knockdown. SIRT1 knockdown decreased the levels of deacetylated PIP5Kγ, PI(4,5)P[subscript 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-PIP5Kγ[subscript gamma] pathway is important for regulating the metabolism of the whole body.

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