The TBC/RabGAP Armus coordinates Rac1 and Rab7 functions during autophagy.
The TBC/RabGAP Armus coordinates Rac1 and Rab7 functions during autophagy.
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DOI：
10.1016/j.devcel.2013.03.005
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发表时间：
2013-04-15
影响因子：
11.8
通讯作者：
Braga, Vania M. M.
中科院分区：
文献类型：
--
作者：
Carroll, Bernadette;Mohd-Naim, Noor;Maximiano, Filipe;Frasa, Marieke A.;McCormack, Jessica;Finelli, Mattea;Thoresen, Sigrid B.;Perdios, Louis;Daigaku, Reiko;Francis, Richard E.;Futter, Clare;Dikic, Ivan;Braga, Vania M. M.
自噬是一个进化上保守的过程，可以实现分解代谢和降解途径。这些途径通常依赖于由Rabs控制的囊泡运输，小的gtp酶被TBC/ rabgap灭活。已知Rac1效应物TBC/RabGAP Armus （TBC1D2A）可抑制Rab7， Rab7是溶酶体功能的关键调节因子。然而，调控自噬的信号和细胞内运输的精确协调尚不清楚。我们发现Armus的过度表达诱导了扩大的自噬体的积累，而Armus的缺失显著延迟了自噬通量。在饥饿诱导的自噬过程中，Rab7被短暂激活。Rab7鸟苷三磷酸/鸟苷二磷酸循环的时空调节是通过Armus与核心自噬调节因子LC3相互作用募集到自噬体发生的。有趣的是，自噬能使Rac1失活。活性Rac1与LC3竞争与Armus的相互作用，从而阻止其适当地招募到自噬体。饥饿期间Rac1和Rab7活动之间的精确协调表明，Armus将自噬与信号和内吞运输结合起来。►自噬强烈灭活Rac1 GTPase并募集TBC/RabGAP Armus►Armus在自噬体上的适当定位需要与LC3结合►Armus抑制延迟自噬通量并增加Rab7·GTP水平►Rac1、Armus和Rab7协调溶酶体与自噬体的有效融合。Rac1效应蛋白Armus是一种GTPase激活蛋白，调节Rab7的功能，从而调节内体向溶酶体的运输。Carroll等人发现Armus直接与核心自噬因子LC3结合，促进自噬体与溶酶体融合，并将局部Rac1活性整合到自噬控制中。
Autophagy is an evolutionarily conserved process that enables catabolic and degradative pathways. These pathways commonly depend on vesicular transport controlled by Rabs, small GTPases inactivated by TBC/RabGAPs. The Rac1 effector TBC/RabGAP Armus (TBC1D2A) is known to inhibit Rab7, a key regulator of lysosomal function. However, the precise coordination of signaling and intracellular trafficking that regulates autophagy is poorly understood. We find that overexpression of Armus induces the accumulation of enlarged autophagosomes, while Armus depletion significantly delays autophagic flux. Upon starvation-induced autophagy, Rab7 is transiently activated. This spatiotemporal regulation of Rab7 guanosine triphosphate/guanosine diphosphate cycling occurs by Armus recruitment to autophagosomes via interaction with LC3, a core autophagy regulator. Interestingly, autophagy potently inactivates Rac1. Active Rac1 competes with LC3 for interaction with Armus and thus prevents its appropriate recruitment to autophagosomes. The precise coordination between Rac1 and Rab7 activities during starvation suggests that Armus integrates autophagy with signaling and endocytic trafficking. ► Autophagy strongly inactivates Rac1 GTPase and recruits the TBC/RabGAP Armus ► Appropriate Armus localization at autophagosomes requires binding to LC3 ► Armus inhibition delays autophagic flux and increases levels of Rab7·GTP ► Rac1, Armus, and Rab7 coordinate efficient lysosome fusion with autophagosomes The Rac1 effector Armus is a GTPase-activating protein that regulates Rab7 function and thus endosomal trafficking to lysosomes. Carroll et al. find that Armus binds directly to the core autophagy factor LC3, facilitates fusion of autophagosomes with lysosomes, and integrates local Rac1 activity into the control of autophagy.
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影响因子：
4
作者：
Jäger, S;Bucci, C;Eskelinen, EL
通讯作者：
Eskelinen, EL
影响因子：
9.2
作者：
Frasa, Marieke A. M.;Maximiano, Filipe C.;Braga, Vania M. M.
通讯作者：
Braga, Vania M. M.
影响因子：
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通讯作者：
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通讯作者：
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作者：
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