饥饿时，ULK对交换因子DENND3的磷酸化作用激活Rab12并诱导自噬。
Phosphorylation of the exchange factor DENND3 by ULK in response to starvation activates Rab12 and induces autophagy.
作者信息
Xu Jie, Fotouhi Maryam, McPherson Peter S
机构信息
Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University, Montreal, Quebec H3A 2B4, Canada
Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University, Montreal, Quebec H3A 2B4, Canada.
出版信息
EMBO Rep. 2015 Jun;16(6):709-18. doi: 10.15252/embr.201440006. Epub 2015 Apr 29.
Abstract
Unc-51-like kinases (ULKs) are the most upstream kinases in the initiation of autophagy, yet the molecular mechanisms underlying their function are poorly understood. We report a new role for ULK in the induction of autophagy. ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. Through binding to LC3 and associating with LC3-positive autophagosomes, active Rab12 facilitates autophagosome trafficking, thus establishing a crucial role for the ULK/DENND3/Rab12 axis in starvation-induced autophagy.
摘要
Unc-51样激酶（ULKs）是自噬起始过程中最上游的激酶，但其功能背后的分子机制仍知之甚少。我们报道了ULK在自噬诱导中的新作用。ULK介导的鸟嘌呤核苷酸交换因子DENND3在丝氨酸554和572处的磷酸化上调了其对小GTP酶Rab12的鸟嘌呤核苷酸交换因子（GEF）活性。通过与LC3结合并与LC3阳性自噬体相关联，活性Rab12促进自噬体运输，从而确立了ULK/DENND3/Rab12轴在饥饿诱导的自噬中的关键作用。
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本文引用的文献
1
The autophagic roles of Rab small GTPases and their upstream regulators: a review.Rab 小 GTP 酶及其上游调节因子的自噬作用：综述
Autophagy. 2014 Jul;10(7):1154-66. doi: 10.4161/auto.29395. Epub 2014 Jun 4.
2
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J Biol Chem. 2014 May 16;289(20):13986-95. doi: 10.1074/jbc.M113.546689. Epub 2014 Apr 9.
3
Rab12 localizes to Shiga toxin-induced plasma membrane invaginations and controls toxin transport.Rab12定位于志贺毒素诱导的质膜内陷处，并控制毒素运输。
Traffic. 2014 Jul;15(7):772-87. doi: 10.1111/tra.12173. Epub 2014 May 5.
4
Regulation of autophagy by the Rab GTPase network.Rab GTPase网络对自噬的调控。
Cell Death Differ. 2014 Mar;21(3):348-58. doi: 10.1038/cdd.2013.187. Epub 2014 Jan 17.
5
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Mol Cell. 2014 Feb 6;53(3):471-83. doi: 10.1016/j.molcel.2013.12.011. Epub 2014 Jan 16.
6
Diverse autophagosome membrane sources coalesce in recycling endosomes.多种自噬体膜来源在再循环内体中融合。
Cell. 2013 Sep 12;154(6):1285-99. doi: 10.1016/j.cell.2013.08.044.
7
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Nat Cell Biol. 2013 Jul;15(7):741-50. doi: 10.1038/ncb2757. Epub 2013 May 19.
8
The role of membrane-trafficking small GTPases in the regulation of autophagy.膜转运小 GTPases 在自噬调节中的作用。
J Cell Sci. 2013 Mar 1;126(Pt 5):1059-69. doi: 10.1242/jcs.123075.
9
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EMBO Rep. 2013 May;14(5):450-7. doi: 10.1038/embor.2013.32. Epub 2013 Mar 12.
10
The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs.C9orf72 基因产物与神经退行性变密切相关，其结构与 DENN Rab-GEFs 具有相关性。
Bioinformatics. 2013 Feb 15;29(4):499-503. doi: 10.1093/bioinformatics/bts725. Epub 2013 Jan 16.
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