Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity

Summary: The mammalian target of rapamycin (mTOR) is a serine-threonine kinase involved in cellular innate immunity, metabolism, and senescence. FK506-binding protein 12 (FKBP12) inhibits mTOR kinase activity via direct association. The FKBP12-mTOR association can be strengthened by the immunosuppre...

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Autores principales:	Lin Hu, Fuxian Chen, Chao Wu, Jun Wang, Si-si Chen, Xiang-rong Li, Jing Wang, Linpeng Wu, Jian-ping Ding, Jian-chuan Wang, Chao Huang, Hui Zheng, Yu Rao, Yu Sun, Zhijie Chang, Wei Deng, Cheng Luo, Y. Eugene Chin
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Biochemistry Protein Molecular biology Science Q
Acceso en línea:	https://doaj.org/article/b2965a81e40b4d1b8790ed81223de156
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spelling	oai:doaj.org-article:b2965a81e40b4d1b8790ed81223de1562021-11-20T05:08:15ZRapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity2589-004210.1016/j.isci.2021.103177https://doaj.org/article/b2965a81e40b4d1b8790ed81223de1562021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221011457https://doaj.org/toc/2589-0042Summary: The mammalian target of rapamycin (mTOR) is a serine-threonine kinase involved in cellular innate immunity, metabolism, and senescence. FK506-binding protein 12 (FKBP12) inhibits mTOR kinase activity via direct association. The FKBP12-mTOR association can be strengthened by the immunosuppressant rapamycin, but the underlying mechanism remains elusive. We show here that the FKBP12-mTOR association is tightly regulated by an acetylation–deacetylation cycle. FKBP12 is acetylated on the lysine cluster (K45/K48/K53) by CREB-binding protein (CBP) in mammalian cells in response to nutrient treatment. Acetyl-FKBP12 associates with CBP acetylated Rheb. Rapamycin recruits SIRT2 with a high affinity for FKBP12 association and deacetylation. SIRT2-deacetylated FKBP12 then switches its association from Rheb to mTOR. Nutrient-activated mTOR phosphorylates IRF3S386 for the antiviral response. In contrast, rapamycin strengthening FKBP12-mTOR association blocks mTOR antiviral activity by recruiting SIRT2 to deacetylate FKBP12. Hence, on/off mTOR activity in response to environmental nutrients relies on FKBP12 acetylation and deacetylation status in mammalian cells.Lin HuFuxian ChenChao WuJun WangSi-si ChenXiang-rong LiJing WangLinpeng WuJian-ping DingJian-chuan WangChao HuangHui ZhengYu RaoYu SunZhijie ChangWei DengCheng LuoY. Eugene ChinElsevierarticleBiochemistryProteinMolecular biologyScienceQENiScience, Vol 24, Iss 11, Pp 103177- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biochemistry Protein Molecular biology Science Q
spellingShingle	Biochemistry Protein Molecular biology Science Q Lin Hu Fuxian Chen Chao Wu Jun Wang Si-si Chen Xiang-rong Li Jing Wang Linpeng Wu Jian-ping Ding Jian-chuan Wang Chao Huang Hui Zheng Yu Rao Yu Sun Zhijie Chang Wei Deng Cheng Luo Y. Eugene Chin Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity
description	Summary: The mammalian target of rapamycin (mTOR) is a serine-threonine kinase involved in cellular innate immunity, metabolism, and senescence. FK506-binding protein 12 (FKBP12) inhibits mTOR kinase activity via direct association. The FKBP12-mTOR association can be strengthened by the immunosuppressant rapamycin, but the underlying mechanism remains elusive. We show here that the FKBP12-mTOR association is tightly regulated by an acetylation–deacetylation cycle. FKBP12 is acetylated on the lysine cluster (K45/K48/K53) by CREB-binding protein (CBP) in mammalian cells in response to nutrient treatment. Acetyl-FKBP12 associates with CBP acetylated Rheb. Rapamycin recruits SIRT2 with a high affinity for FKBP12 association and deacetylation. SIRT2-deacetylated FKBP12 then switches its association from Rheb to mTOR. Nutrient-activated mTOR phosphorylates IRF3S386 for the antiviral response. In contrast, rapamycin strengthening FKBP12-mTOR association blocks mTOR antiviral activity by recruiting SIRT2 to deacetylate FKBP12. Hence, on/off mTOR activity in response to environmental nutrients relies on FKBP12 acetylation and deacetylation status in mammalian cells.
format	article
author	Lin Hu Fuxian Chen Chao Wu Jun Wang Si-si Chen Xiang-rong Li Jing Wang Linpeng Wu Jian-ping Ding Jian-chuan Wang Chao Huang Hui Zheng Yu Rao Yu Sun Zhijie Chang Wei Deng Cheng Luo Y. Eugene Chin
author_facet	Lin Hu Fuxian Chen Chao Wu Jun Wang Si-si Chen Xiang-rong Li Jing Wang Linpeng Wu Jian-ping Ding Jian-chuan Wang Chao Huang Hui Zheng Yu Rao Yu Sun Zhijie Chang Wei Deng Cheng Luo Y. Eugene Chin
author_sort	Lin Hu
title	Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity
title_short	Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity
title_full	Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity
title_fullStr	Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity
title_full_unstemmed	Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity
title_sort	rapamycin recruits sirt2 for fkbp12 deacetylation during mtor activity modulation in innate immunity
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/b2965a81e40b4d1b8790ed81223de156
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Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity

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