SIRT1 Regulates Thyroid-Stimulating Hormone Release by Enhancing PIP5K[gamma] Activity through Deacetylation of Specific Lysine Residues in Mammals

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. Here, we report that SIRT1 is abundantly expressed in pituitary thyrotropes and regulates...

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Published inPloS one Vol. 5; no. 7; p. e11755
Main Authors 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, Guarente, Leonard, Setou, Mitsutoshi
Format Journal Article
LanguageEnglish
Published Public Library of Science 23.07.2010
Subjects
Enzymes
Lysine
Phosphates
Physiological aspects
Thyrotropin
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Summary: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. 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 PIP5K[gamma] and enhanced PIP5K[gamma] enzyme activity. SIRT1-mediated TSH secretion was abolished by PIP5K[gamma] knockdown. SIRT1 knockdown decreased the levels of deacetylated PIP5K[gamma], PI(4,5)P.sub.2, and reduced the secretion of TSH from pituitary cells. These results were also observed in SIRT1-knockout mice. Our findings indicated that the control of TSH release by the SIRT1-PIP5K[gamma] pathway is important for regulating the metabolism of the whole body.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0011755