Tumor suppressor Spred2 interaction with LC3 promotes autophagosome maturation and induces autophagy-dependent cell death.
Tumor suppressor Spred2 interaction with LC3 promotes autophagosome maturation and induces autophagy-dependent cell death.
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肿瘤抑制因子 Spred2 与 LC3 相互作用促进自噬体成熟并诱导自噬依赖性细胞死亡
DOI：
10.18632/oncotarget.8357
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发表时间：
2016-05-03
期刊：
影响因子：
--
通讯作者：
Meng S
中科院分区：
文献类型：
--
作者：
Jiang K;Liu M;Lin G;Mao B;Cheng W;Liu H;Gal J;Zhu H;Yuan Z;Deng W;Liu Q;Gong P;Bi X;Meng S
肿瘤抑制因子Spred2 （Sprouty-related EVH1结构域-2）在多种癌症中诱导细胞死亡。然而，潜在的机制仍有待阐明。本研究表明，Spred2在人宫颈癌HeLa和肺癌A549细胞中诱导caspase不依赖但自噬依赖的细胞死亡。我们发现异位Spred2增加了A549和HeLa细胞中微管相关蛋白1轻链3 （LC3）的转化、GFP-LC3斑点的形成和p62/SQSTM1的降解。相反，肿瘤细胞中Spred2的下调抑制了自噬诱导剂雷帕霉素诱导的自噬体成熟的上调，这可以通过挽救Spred2来逆转。这些数据表明Spred2促进肿瘤细胞的自噬。机制上，Spred2通过其SPR结构域的LC3相互作用区（LIR）基序与LC3共定位并相互作用。LIR基序的突变或SPR结构域的缺失会损害Spred2介导的自噬体成熟和肿瘤细胞死亡，这表明Spred2触发肿瘤细胞死亡需要功能LIR。此外，Spred2通过其SPR结构域与p62/SQSTM1相互作用并共定位。此外，Spred2、p62和LAMP2在HeLa细胞中的共定位表明，p62可能参与了Spred2介导的自噬体成熟。使用溶酶体抑制剂氯喹抑制自噬，减少spred2介导的HeLa细胞死亡。在HeLa和A549细胞中沉默自噬相关基因ATG5、LC3或p62的表达得到了类似的结果，这表明spred2诱导的肿瘤细胞死亡需要自噬。综上所述，这些数据表明Spred2以自噬依赖的方式诱导肿瘤细胞死亡。
The tumor suppressor Spred2 (Sprouty-related EVH1 domain-2) induces cell death in a variety of cancers. However, the underlying mechanism remains to be elucidated. Here we show that Spred2 induces caspase-independent but autophagy-dependent cell death in human cervical carcinoma HeLa and lung cancer A549 cells. We demonstrate that ectopic Spred2 increased both the conversion of microtubule-associated protein 1 light chain 3 (LC3), GFP-LC3 puncta formation and p62/SQSTM1 degradation in A549 and HeLa cells. Conversely, knockdown of Spred2 in tumor cells inhibited upregulation of autophagosome maturation induced by the autophagy inducer Rapamycin, which could be reversed by the rescue Spred2. These data suggest that Spred2 promotes autophagy in tumor cells. Mechanistically, Spred2 co-localized and interacted with LC3 via the LC3-interacting region (LIR) motifs in its SPR domain. Mutations in the LIR motifs or deletion of the SPR domain impaired Spred2-mediated autophagosome maturation and tumor cell death, indicating that functional LIR is required for Spred2 to trigger tumor cell death. Additionally, Spred2 interacted and co-localized with p62/SQSTM1 through its SPR domain. Furthermore, the co-localization of Spred2, p62 and LAMP2 in HeLa cells indicates that p62 may be involved in Spred2-mediated autophagosome maturation. Inhibition of autophagy using the lysosomal inhibitor chloroquine, reduced Spred2-mediated HeLa cell death. Silencing the expression of autophagy-related genes ATG5, LC3 or p62 in HeLa and A549 cells gave similar results, suggesting that autophagy is required for Spred2-induced tumor cell death. Collectively, these data indicate that Spred2 induces tumor cell death in an autophagy-dependent manner.
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影响因子：
16
作者：
Kirkin, Vladimir;Lamark, Trond;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
4
作者：
Mizushima, N;Kuma, A;Yoshimori, T
通讯作者：
Yoshimori, T
影响因子：
4.8
作者：
Jain, Ashish;Lamark, Trond;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
3.5
作者：
Kametaka, S;Matsuura, A;Ohsumi, Y
通讯作者：
Ohsumi, Y
Spred2 与晚期内体蛋白 NBR1 的相互作用下调成纤维细胞生长因子受体信号传导。
DOI：
10.1083/jcb.200905118
发表时间：
2009-10-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mardakheh FK;Yekezare M;Machesky LM;Heath JK
通讯作者：
Heath JK