Flightless-I Blocks p62-Mediated Recognition of LC3 to Impede Selective Autophagy and Promote Breast Cancer Progression
Flightless-I Blocks p62-Mediated Recognition of LC3 to Impede Selective Autophagy and Promote Breast Cancer Progression
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Flightless-I 阻断 p62 介导的 LC3 识别，从而阻碍选择性自噬并促进乳腺癌进展。
DOI：
10.1158/0008-5472.can-17-3835
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发表时间：
2018-09-01
期刊：
影响因子：
11.2
通讯作者：
Chen, Hang-Zi
中科院分区：
文献类型：
--
作者：
He, Jian-Ping;Hou, Pei-Pei;Chen, Hang-Zi
p62是一种通过与自噬体上的货物和LC 3蛋白同时相互作用以维持细胞内稳态而促进选择性自噬的受体。然而，这一过程背后的调控机制及其与乳腺癌的关系仍有待阐明。在这里，我们报告说，Flightless-I（FliI），一种新的p62相互作用蛋白，通过阻碍选择性自噬促进乳腺癌的进展。FliI在临床乳腺癌样品中高度表达，并且FliI的杂合缺失延缓了PyVT小鼠乳腺肿瘤的发展。FliI诱导p62募集的货物进入Triton X-100不溶性组分（TI）形成聚集体，从而阻断p62对LC 3的识别并阻碍p62依赖性选择性自噬。Flil的这种功能通过Akt介导的Ser 436磷酸化而增强，并通过Ulk 1在Ser 64的磷酸化而抑制。FliI对p62-募集货物的自噬清除的阻碍与蛋白质和DNA上的氧化损伤的积累有关，这可能有助于癌症的发展。FliI的杂合敲除促进了聚集体的选择性自噬清除，ROS水平的降低和蛋白质氧化损伤，最终延缓乳腺癌的进展。在临床乳腺癌样本中，Akt介导的FliI在Ser 436的磷酸化与长期预后呈负相关，而Ulk 1诱导的FliI在Ser 64的磷酸化与临床结果呈正相关。总之，这项工作表明，FliI作为一个检查点蛋白的功能，选择性自噬之间的串扰FliI和p62招募货物，其磷酸化可能作为一个预后标记乳腺癌。意义：Flightless-I功能作为一个检查点蛋白的选择性自噬与p62相互作用，以阻止其识别的LC 3，导致肿瘤发生在乳腺癌。78（17）; 4853-64.©2018 AACR.
p62 is a receptor that facilitates selective autophagy by interacting simultaneously with cargoes and LC3 protein on the autophagosome to maintain cellular homeostasis. However, the regulatory mechanism(s) behind this process and its association with breast cancer remain to be elucidated. Here, we report that Flightless-I (FliI), a novel p62-interacting protein, promotes breast cancer progression by impeding selective autophagy. FliI was highly expressed in clinical breast cancer samples, and heterozygous deletion of FliI retarded the development of mammary tumors in PyVT mice. FliI induced p62-recruited cargoes into Triton X-100 insoluble fractions (TI) to form aggregates, thereby blocking p62 recognition of LC3 and hindering p62-dependent selective autophagy. This function of Flil was reinforced by Akt-mediated phosphorylation at Ser436 and inhibited by phosphorylation of Ulk1 at Ser64. Obstruction of autophagic clearance of p62-recruited cargoes by FliI was associated with the accumulation of oxidative damage on proteins and DNA, which could contribute to the development of cancer. Heterozygous knockout of FliI facilitated selectively autophagic clearance of aggregates, abatement of ROS levels, and protein oxidative damage, ultimately retarding mammary cancer progression. In clinical breast cancer samples, Akt-mediated phosphorylation of FliI at Ser436 negatively correlated with long-term prognosis, while Ulk1-induced FliI phosphorylation at Ser64 positively correlated with clinical outcome. Together, this work demonstrates that FliI functions as a checkpoint protein for selective autophagy in the crosstalk between FliI and p62-recruited cargoes, and its phosphorylation may serve as a prognostic marker for breast cancer.Significance: Flightless-I functions as a checkpoint protein for selective autophagy by interacting with p62 to block its recognition of LC3, leading to tumorigenesis in breast cancer.Cancer Res; 78(17); 4853-64. ©2018 AACR.