Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity.
Biochemistry
Molecular biology
Protein
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
19 Nov 2021
19 Nov 2021
Historique:
received:
26
05
2020
revised:
17
08
2021
accepted:
23
09
2021
entrez:
29
10
2021
pubmed:
30
10
2021
medline:
30
10
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34712915
doi: 10.1016/j.isci.2021.103177
pii: S2589-0042(21)01145-7
pmc: PMC8529501
doi:
Types de publication
Journal Article
Langues
eng
Pagination
103177Informations de copyright
© 2021 The Authors.
Déclaration de conflit d'intérêts
The authors declare no competing interests.
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