TY - JOUR
T1 - SIRT1 regulates thyroid-stimulating hormone release by enhancing PIP5Kγ activity through deacetylation of specific lysine residues in mammals
AU - Akieda-Asai, Sayaka
AU - Zaima, Nobuhiro
AU - Ikegami, Koji
AU - Kahyo, Tomoaki
AU - Yao, Ikuko
AU - Hatanaka, Takahiro
AU - Iemura, Shun ichiro
AU - Sugiyama, Rika
AU - Yokozeki, Takeaki
AU - Eishi, Yoshinobu
AU - Koike, Morio
AU - Ikeda, Kyoji
AU - Chiba, Takuya
AU - Yamaza, Haruyoshi
AU - Shimokawa, Isao
AU - Song, Si Young
AU - Matsuno, Akira
AU - Mizutani, Akiko
AU - Sawabe, Motoji
AU - Chao, Moses V.
AU - Tanaka, Masashi
AU - Kanaho, Yasunori
AU - Natsume, Tohru
AU - Sugimura, Haruhiko
AU - Date, Yukari
AU - Mcburney, Michael W.
AU - Guarente, Leonard
AU - Setou, Mitsutoshi
PY - 2010
Y1 - 2010
N2 - 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)y was identified as a SIRT1 binding partner and deacetylation substrate. SIRT1 deacetylated two specific lysine residues (K265/K268) in PIP5Ky and enhanced PIP5Ky enzyme activity. SIRT1-mediated TSH secretion was abolished by PIP5Ky knockdown. SIRT1 knockdown decreased the levels of deacetylated PIP5Ky, PI(4,5)P2, 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 pathway is important for regulating the metabolism of the whole body.
AB - 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)y was identified as a SIRT1 binding partner and deacetylation substrate. SIRT1 deacetylated two specific lysine residues (K265/K268) in PIP5Ky and enhanced PIP5Ky enzyme activity. SIRT1-mediated TSH secretion was abolished by PIP5Ky knockdown. SIRT1 knockdown decreased the levels of deacetylated PIP5Ky, PI(4,5)P2, 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 pathway is important for regulating the metabolism of the whole body.
UR - http://www.scopus.com/inward/record.url?scp=77955452426&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955452426&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0011755
DO - 10.1371/journal.pone.0011755
M3 - Article
C2 - 20668706
AN - SCOPUS:77955452426
SN - 1932-6203
VL - 5
JO - PLoS One
JF - PLoS One
IS - 7
M1 - e11755
ER -