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

doi:10.1016/j.isci.2021.103177

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

iScience. 2021 Sep 27;24(11):103177. doi: 10.1016/j.isci.2021.103177. eCollection 2021 Nov 19.

Authors

Lin Hu¹, Fuxian Chen¹, Chao Wu¹, Jun Wang², Si-Si Chen³, Xiang-Rong Li¹, Jing Wang¹, Linpeng Wu¹, Jian-Ping Ding³, Jian-Chuan Wang⁴, Chao Huang³, Hui Zheng¹, Yu Rao⁵, Yu Sun³, Zhijie Chang⁵, Wei Deng⁶, Cheng Luo², Y Eugene Chin¹

Affiliations

¹ Institutes of Biological and Medical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China.
² Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ Institute of Biochemistry and Cell Biology and Institute of Nutrition and Health Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
⁴ Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
⁵ Laboratory of Membrane Biology, School of Medicine and School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
⁶ Hematology center, cyrus Tang medical institute, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China.

Abstract

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.

Keywords: Biochemistry; Molecular biology; Protein.