FGF7/KGF regulates autophagy in keratinocytes: A novel dual role in the induction of both assembly and turnover of autophagosomes.
FGF7/KGF regulates autophagy in keratinocytes: A novel dual role in the induction of both assembly and turnover of autophagosomes.
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DOI：
10.4161/auto.28145
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发表时间：
2014-05
期刊：
影响因子：
13.3
通讯作者：
Torrisi MR
中科院分区：
文献类型：
--
作者：
Belleudi F;Purpura V;Caputo S;Torrisi MR
自噬是细胞在分化过程中克服应激条件并迅速改变其表型的降解途径。尽管自噬具有保护作用，但当其加剧时，自噬可能导致细胞死亡。参与细胞存活和阻止分化的几种生长因子能够抑制自噬。在这里，我们研究了FGF 7/KGF的自噬作用，在上皮细胞的保护和分化的重要球员。生物化学和定量荧光方法显示，FGF 7及其信号传导诱导人角质形成细胞中的自噬，并且特异性抑制剂的使用表明这种作用不依赖于PI 3 K-AKT-MTOR途径。自噬体与溶酶体融合的选择性阻断阐明了FGF 7诱导自噬刺激自噬体形成。然而，定量荧光方法也表明，在长时间的自噬刺激下，FGF 7能够加速自噬体的周转。此外，在分化角质形成细胞中，自噬抑制剂3-MA的使用以及BECN 1和ATG 5（该过程的2种必需调节剂）的消耗抵消了FGF 7诱导的分化标记物KRT 1/K1的增加，表明自噬是FGF 7介导的早期分化所需的。这些结果提供了FGF 7在调节自噬过程的连续步骤中的作用的第一个证据，并加强了自噬和分化之间直接相互作用的假设。另一方面，FGF 7加速自噬体周转，防止其危险积累的能力与生长因子在上皮细胞中发挥的公认的保护作用一致。
Autophagy is a degradative pathway through which cells overcome stressful conditions and rapidly change their phenotype during differentiation. Despite its protective role, when exacerbated, autophagy may lead to cell death. Several growth factors involved in cell survival and in preventing differentiation are able to inhibit autophagy. Here we investigated the autophagic role of FGF7/KGF, an important player in epithelial cell protection and differentiation. Biochemical and quantitative fluorescence approaches showed that FGF7 and its signaling induce autophagy in human keratinocytes and the use of specific inhibitors indicated that this effect is independent of the PI3K-AKT-MTOR pathway. The selective block of autophagosome-to-lysosome fusion clarified that FGF7 induces autophagy stimulating autophagosome formation. However, quantitative fluorescence approaches also indicated that, upon a prolonged autophagic stimulus, FGF7 is able to accelerate autophagosome turnover. Moreover, in differentiating keratinocytes, the use of the autophagic inhibitor 3-MA as well as the depletion of BECN1 and ATG5, 2 essential regulators of the process, counteracted the FGF7-induced increase of the differentiation marker KRT1/K1, suggesting that autophagy is required for the FGF7-mediated early differentiation. These results provide the first evidence of a role of FGF7 in the regulation of sequential steps of the autophagic process and strengthen the hypothesis of a direct interplay between autophagy and differentiation. On the other hand, the ability of FGF7 to accelerate autophagosome turnover, preventing their dangerous accumulation, is consistent with the well-established protective role played by the growth factor in epithelial cells.
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作者：
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