Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity.
Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity.
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雷帕霉素在先天免疫中的 mTOR 活性调节过程中招募 SIRT2 进行 FKBP12 脱乙酰化
DOI：
10.1016/j.isci.2021.103177
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发表时间：
2021-11-19
期刊：
影响因子：
5.8
通讯作者：
Chin YE
中科院分区：
文献类型：
--
作者：
Hu L;Chen F;Wu C;Wang J;Chen SS;Li XR;Wang J;Wu L;Ding JP;Wang JC;Huang C;Zheng H;Rao Y;Sun Y;Chang Z;Deng W;Luo C;Chin YE
哺乳动物雷帕霉素靶蛋白（mTOR）是一种丝氨酸-苏氨酸激酶，参与细胞先天免疫、代谢和衰老。FK 506结合蛋白12（FKBP 12）通过直接结合抑制mTOR激酶活性。免疫抑制剂雷帕霉素可以加强FKBP 12-mTOR的结合，但其潜在机制仍然难以捉摸。我们在这里表明，FKBP 12-mTOR的结合受到乙酰化-脱乙酰化循环的严格调节。在哺乳动物细胞中，FKBP 12在营养处理后被CREB结合蛋白（CBP）在赖氨酸簇（K45/K48/K53）上乙酰化。乙酰基-FKBP 12与CBP乙酰化Rheb缔合。雷帕霉素以对FKBP 12缔合和脱乙酰化的高亲和力募集SIRT 2。SIRT 2-脱乙酰化的FKBP 12然后将其缔合从Rheb转换为mTOR。营养激活的mTOR磷酸化IRF 3S 386用于抗病毒反应。相比之下，雷帕霉素增强FKBP 12-mTOR缔合通过募集SIRT 2使FKBP 12脱乙酰化来阻断mTOR抗病毒活性。因此，响应于环境营养物的开/关mTOR活性依赖于哺乳动物细胞中的FKBP 12乙酰化和脱乙酰化状态。FKBP 12-mTOR的结合受乙酰化-脱乙酰化循环的严格调节SIRT 2负责FKBP 12的脱乙酰化Rheb的乙酰化是mTOR激活所必需的mTOR磷酸化IRF 3 S386用于I型干扰素基因表达生物化学;蛋白质;分子生物学
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. 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
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