Regulation of the autophagy protein LC3 by phosphorylation.
Regulation of the autophagy protein LC3 by phosphorylation.
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DOI：
10.1083/jcb.201002108
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发表时间：
2010-08-23
期刊：
影响因子：
--
通讯作者：
Chu CT
中科院分区：
文献类型：
--
作者：
Cherra SJ 3rd;Kulich SM;Uechi G;Balasubramani M;Mountzouris J;Day BW;Chu CT
PKA通过抑制LC3向自噬体的招募来抑制自噬。巨噬是影响细胞存活、分化、肿瘤发生和神经退行性变的主要分解代谢途径。虽然在饥饿期间，体降解维持碳源，但自噬有助于分化的神经元过程的收缩。自噬相关基因的鉴定促进了对微管相关蛋白1轻链3 （LC3）在自噬诱导中的募集的快速了解，尽管对其抑制机制的了解仍然较少。通过质谱分析，我们在LC3上发现了一个直接的蛋白激酶a （PKA）磷酸化位点，该位点调节其参与自噬。代谢性（雷帕霉素）和病理性（MPP+）自噬诱导剂均可引起内源性LC3的去磷酸化。假磷酸化的LC3突变体对自噬体的招募减少，而非磷酸化的突变体对点的形成增强。最后，在富含亮氨酸的重复激酶2中表达帕金森病相关G2019S突变诱导的自噬依赖性神经突缩短被二丁基环腺苷单磷酸、PKA催化亚基的细胞质表达或LC3磷酸化模拟物抑制。这些数据证明了磷酸化在调节LC3活性中的作用。
PKA puts the brakes on autophagy by inhibiting LC3 recruitment to autophagosomes. Macroautophagy is a major catabolic pathway that impacts cell survival, differentiation, tumorigenesis, and neurodegeneration. Although bulk degradation sustains carbon sources during starvation, autophagy contributes to shrinkage of differentiated neuronal processes. Identification of autophagy-related genes has spurred rapid advances in understanding the recruitment of microtubule-associated protein 1 light chain 3 (LC3) in autophagy induction, although braking mechanisms remain less understood. Using mass spectrometry, we identified a direct protein kinase A (PKA) phosphorylation site on LC3 that regulates its participation in autophagy. Both metabolic (rapamycin) and pathological (MPP+) inducers of autophagy caused dephosphorylation of endogenous LC3. The pseudophosphorylated LC3 mutant showed reduced recruitment to autophagosomes, whereas the nonphosphorylatable mutant exhibited enhanced puncta formation. Finally, autophagy-dependent neurite shortening induced by expression of a Parkinson disease–associated G2019S mutation in leucine-rich repeat kinase 2 was inhibited by dibutyryl–cyclic adenosine monophosphate, cytoplasmic expression of the PKA catalytic subunit, or the LC3 phosphorylation mimic. These data demonstrate a role for phosphorylation in regulating LC3 activity.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
--
作者：
Chu, Charleen T.;Plowey, Edward D.;Dagda, Ruben K.;Hickey, Robert W.;Cherra, Salvatore J., III;Clark, Robert S. B.
通讯作者：
Clark, Robert S. B.
影响因子：
6
作者：
Zhu, Jian-hui;Horbinski, Craig;Chu, Charleen T.
通讯作者：
Chu, Charleen T.
影响因子：
2.1
作者：
Sugawara, K;Suzuki, NN;Inagaki, F
通讯作者：
Inagaki, F
影响因子：
10.6
作者：
Boland, Barry;Nixon, Ralph A.
通讯作者：
Nixon, Ralph A.