Rapid mitogenic regulation of the mTORC1 inhibitor, DEPTOR, by phosphatidic acid.
Rapid mitogenic regulation of the mTORC1 inhibitor, DEPTOR, by phosphatidic acid.
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磷脂酸对 mTORC1 抑制剂 DEPTOR 的快速有丝分裂调节。
DOI：
10.1016/j.molcel.2015.03.028
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发表时间：
2015
期刊：
影响因子：
16
通讯作者：
Chen,Jie
中科院分区：
文献类型：
--
作者：
Yoon,Mee-Sup;Rosenberger,ChristinaL;Wu,Cong;Truong,Nga;Sweedler,JonathanV;Chen,Jie
雷帕霉素复合体1的哺乳动物靶点(MTORC1)部分受内源性抑制物DEPTOR的调节。然而，DEPTOR调节mTORC1快速激活的机制仍不清楚。我们报道了DEPTOR在有丝分裂刺激下迅速和暂时地从mTORC1上解离，这表明了急性mTORC1激活的机制。这种有丝分裂原刺激的DEPTOR解离可通过抑制或耗尽mTORC1调节因子磷脂酶D(PLD)来阻止，并与PLD产物磷脂酸(PA)一起重复。我们的质谱分析已经独立地确定DEPTOR是由PA解离的mTOR结合伙伴。有趣的是，只有含有不饱和脂肪酸链的PA物种，如PLD产生的物种，才能取代DEPTOR并激活mTORC1，与mTOR的FRB结构域具有高亲和力。我们的发现揭示了mTOR的调节机制，并为PA功能的精致特异性提供了分子解释。
The mammalian target of rapamycin complex 1 (mTORC1) is regulated, in part, by the endogenous inhibitor DEPTOR. However, the mechanism of DEPTOR regulation with regard to rapid mTORC1 activation remains unknown. We report that DEPTOR is rapidly and temporarily dissociated from mTORC1 upon mitogenic stimulation, suggesting a mechanism underlying acute mTORC1 activation. This mitogen-stimulated DEPTOR dissociation is blocked by inhibition or depletion of the mTORC1 regulator, phospholipase D (PLD), and recapitulated with the addition of the PLD product phosphatidic acid (PA). Our mass spectrometry analysis has independently identified DEPTOR as an mTOR binding partner dissociated by PA. Interestingly, only PA species with unsaturated fatty acid chains, such as those produced by PLD, are capable of displacing DEPTOR and activating mTORC1, with high affinity for the FRB domain of mTOR. Our findings reveal a mechanism of mTOR regulation and provide a molecular explanation for the exquisite specificity of PA function.
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