Interaction of caveolin-1 with ATG12-ATG5 system suppresses autophagy in lung epithelial cells
Interaction of caveolin-1 with ATG12-ATG5 system suppresses autophagy in lung epithelial cells
复制标题
Caveolin-1 与 ATG12-ATG5 系统的相互作用抑制肺上皮细胞的自噬
DOI：
10.1152/ajplung.00268.2013
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发表时间：
2014-06-01
影响因子：
4.9
通讯作者：
Shen, Hua-Hao
中科院分区：
文献类型：
--
作者：
Chen, Zhi-Hua;Cao, Jiao-Fei;Shen, Hua-Hao
自噬在细胞稳态和对不利环境的适应中起着关键作用，尽管这一过程的调控尚不完全清楚。我们最近观察到，作为质膜脂筏的主要成分，Cav-1可以调节吸烟引起的肺上皮损伤中的自噬，尽管其潜在的分子机制尚不完全清楚。在本研究中，我们发现Cav-1与肺上皮Beas-2B细胞中的ATG12-ATG5相互作用并调节ATG12-ATG5的表达，ATG12-ATG5是一种泛素样偶联系统，对自噬体的形成至关重要。Cav-1的缺失增加了基础和饥饿诱导的ATG12-ATG5水平和自噬。生化分析表明，Cav-1与ATG5、ATG12及其活性复合物ATG12-ATG5相互作用。ATG5或ATG12的过表达增加了它们与Cav-1的相互作用，ATG12-ATG5偶联物的形成以及随后的基础自噬水平，但导致Cav-1与另一分子的相互作用降低。ATG12的敲低增强了ATG5-Cav-1的相互作用。ATG12上Cav-1结合基序的突变破坏了它们的相互作用，进一步增强了自噬。Cav-1还调节另一种在自噬体形成过程中与ATG12ATG5偶联物相关的自噬蛋白ATG16L的表达。总之，这些研究清楚地表明，Cav-1与ATG12-ATG5系统竞争性相互作用，抑制后者在肺上皮细胞中的形成和功能，从而为Cav-1调节自噬的分子机制提供了新的见解，并提示Cav-1通过调节自噬稳态在某些肺部疾病中的重要作用。
Autophagy plays a pivotal role in cellular homeostasis and adaptation to adverse environments, although the regulation of this process remains incompletely understood. We have recently observed that caveolin-1 (Cav-1), a major constituent of lipid rafts on plasma membrane, can regulate autophagy in cigarette smoking-induced injury of lung epithelium, although the underlying molecular mechanisms remain incompletely understood. In the present study we found that Cav-1 interacted with and regulated the expression of ATG12-ATG5, an ubiquitin-like conjugation system crucial for autophagosome formation, in lung epithelial Beas-2B cells. Deletion of Cav-1 increased basal and starvation-induced levels of ATG12-ATG5 and autophagy. Biochemical analyses revealed that Cav-1 interacted with ATG5, ATG12, and their active complex ATG12-ATG5. Overexpression of ATG5 or ATG12 increased their interactions with Cav-1, the formation of ATG12-ATG5 conjugate, and the subsequent basal levels of autophagy but resulted in decreased interactions between Cav-1 and another molecule. Knockdown of ATG12 enhanced the ATG5-Cav-1 interaction. Mutation of the Cav-1 binding motif on ATG12 disrupted their interaction and further augmented autophagy. Cav-1 also regulated the expression of ATG16L, another autophagy protein associating with the ATG12ATG5 conjugate during autophagosome formation. Altogether these studies clearly demonstrate that Cav-1 competitively interacts with the ATG12-ATG5 system to suppress the formation and function of the latter in lung epithelial cells, thereby providing new insights into the molecular mechanisms by which Cav-1 regulates autophagy and suggesting the important function of Cav-1 in certain lung diseases via regulation of autophagy homeostasis.