RT Journal Article
SR Electronic
T1 Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 958
OP 968
DO 10.4049/jimmunol.1302341
VO 192
IS 3
A1 Takasaka, Naoki
A1 Araya, Jun
A1 Hara, Hiromichi
A1 Ito, Saburo
A1 Kobayashi, Kenji
A1 Kurita, Yusuke
A1 Wakui, Hiroshi
A1 Yoshii, Yutaka
A1 Yumino, Yoko
A1 Fujii, Satoko
A1 Minagawa, Shunsuke
A1 Tsurushige, Chikako
A1 Kojima, Jun
A1 Numata, Takanori
A1 Shimizu, Kenichiro
A1 Kawaishi, Makoto
A1 Kaneko, Yumi
A1 Kamiya, Noriki
A1 Hirano, Jun
A1 Odaka, Makoto
A1 Morikawa, Toshiaki
A1 Nishimura, Stephen L.
A1 Nakayama, Katsutoshi
A1 Kuwano, Kazuyoshi
YR 2014
UL http://www.jimmunol.org/content/192/3/958.abstract
AB Cigarette smoke (CS)–induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.