Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity
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
Affiliations
Lin Hu
Institutes of Biological and Medical Sciences, Soochow University, 199 Ren’ai Road, Suzhou, Jiangsu 215123, China
Fuxian Chen
Institutes of Biological and Medical Sciences, Soochow University, 199 Ren’ai Road, Suzhou, Jiangsu 215123, China
Chao Wu
Institutes of Biological and Medical Sciences, Soochow University, 199 Ren’ai Road, Suzhou, Jiangsu 215123, China
Jun Wang
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Si-si Chen
Institute of Biochemistry and Cell Biology and Institute of Nutrition and Health Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
Xiang-rong Li
Institutes of Biological and Medical Sciences, Soochow University, 199 Ren’ai Road, Suzhou, Jiangsu 215123, China
Jing Wang
Institutes of Biological and Medical Sciences, Soochow University, 199 Ren’ai Road, Suzhou, Jiangsu 215123, China
Linpeng Wu
Institutes of Biological and Medical Sciences, Soochow University, 199 Ren’ai Road, Suzhou, Jiangsu 215123, China
Jian-ping Ding
Institute of Biochemistry and Cell Biology and Institute of Nutrition and Health Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
Jian-chuan Wang
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA
Chao Huang
Institute of Biochemistry and Cell Biology and Institute of Nutrition and Health Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
Hui Zheng
Institutes of Biological and Medical Sciences, Soochow University, 199 Ren’ai Road, Suzhou, Jiangsu 215123, China
Yu Rao
Laboratory of Membrane Biology, School of Medicine and School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
Yu Sun
Institute of Biochemistry and Cell Biology and Institute of Nutrition and Health Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
Zhijie Chang
Laboratory of Membrane Biology, School of Medicine and School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
Wei Deng
Hematology center, cyrus Tang medical institute, Soochow University, 199 Ren’ai Road, Suzhou, Jiangsu 215123, China; Corresponding author
Cheng Luo
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Corresponding author
Y. Eugene Chin
Institutes of Biological and Medical Sciences, Soochow University, 199 Ren’ai Road, Suzhou, Jiangsu 215123, China; Corresponding author
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.
