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

ABSTRACT: 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. Graphical abstract Highlights • FKBP12-mTOR association is tightly regulated by an acetylation–deacetylation cycle• SIRT2 is responsible for FKBP12 deacetylation• Acetylation of Rheb is indispensable to mTOR activation• mTOR phosphorylates IRF3 S386 for type-I interferon gene expression Biochemistry; Protein; Molecular biology

SUBMITTER: Hu L

PROVIDER: S-EPMC8529501 | biostudies-literature |

REPOSITORIES: biostudies-literature

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