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

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

doi:10.1371/journal.pone.0011755

Abstract

BackgroundSIRT1, 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 FindingsHere, 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 was identified as a SIRT1 binding partner and deacetylation substrate. SIRT1 deacetylated two specific lysine residues (K265/K268) in PIP5Kγ and enhanced PIP5Kγ enzyme activity. SIRT1-mediated TSH secretion was abolished by PIP5Kγ knockdown. SIRT1 knockdown decreased the levels of deacetylated PIP5Kγ, PI(4,5)P2, and reduced the secretion of TSH from pituitary cells. These results were also observed in SIRT1-knockout mice.Conclusions/SignificanceOur findings indicated that the control of TSH release by the SIRT1-PIP5Kγ pathway is important for regulating the metabolism of the whole body.

Highlights

IntroductionSir (silent information regulator 2) is a NAD+-dependent protein deacetylase [1,2]
Sir2 is a NAD+-dependent protein deacetylase [1,2]
Conclusions/Significance: Our findings indicated that the control of thyroid-stimulating hormone (TSH) release by the SIRT1-PIP5Kc pathway is important for regulating the metabolism of the whole body

Summary

Introduction

Sir (silent information regulator 2) is a NAD+-dependent protein deacetylase [1,2]. Sir mediates transcriptional silencing at telomeres and regulates the pace of aging [3]. SIRT1, the closest mammalian orthologue of Sir, has diverse roles in a variety of organs or tissues [5], and molecular mechanisms underlying the broad SIRT1 functions are highly complicated. SIRT1 is shown to be mainly involved in the regulations of whole body metabolism and physical activity. SIRT1, a NAD-dependent deacetylase, has diverse roles in a variety of organs such as regulation of endocrine function and metabolism. It remains to be addressed how it regulates hormone release there

Methods

Results

Conclusion