SIRT1 Regulates Thyroid-Stimulating Hormone Release by Enhancing PIP5Kgamma 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.


RESULTS
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
Our findings indicated that the control of TSH release by the SIRT1-PIP5Kgamma pathway is important for regulating the metabolism of the whole body.
Akieda-Asai
Sayaka
S
Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan.
Zaima
Nobuhiro
N
Ikegami
Koji
K
Kahyo
Tomoaki
T
Yao
Ikuko
I
Hatanaka
Takahiro
T
Iemura
Shun-Ichiro
S
Sugiyama
Rika
R
Yokozeki
Takeaki
T
Eishi
Yoshinobu
Y
Koike
Morio
M
Ikeda
Kyoji
K
Chiba
Takuya
T
Yamaza
Haruyoshi
H
Shimokawa
Isao
I
Song
Si-Young
SY
Matsuno
Akira
A
Mizutani
Akiko
A
Sawabe
Motoji
M
Chao
Moses V
MV
Tanaka
Masashi
M
Kanaho
Yasunori
Y
Natsume
Tohru
T
Sugimura
Haruhiko
H
Date
Yukari
Y
McBurney
Michael W
MW
Guarente
Leonard
L
Setou
Mitsutoshi
M
D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D018274:Electroporation; D005838:Genotype; D006801:Humans; D047468:Immunoprecipitation; D008239:Lysine / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013972:Thyrotropin / Q000378:metabolism*
D013972:Thyrotropin; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D056564:Sirtuin 1; D008239:Lysine