Ambra1 is considered an autophagy and trafficking protein with roles in neurogenesis and cancer cell invasion. Here, we report that Ambra1 also localizes to the nucleus of cancer cells, where it has a novel nuclear scaffolding function that controls gene expression. Using biochemical fractionation and proteomics, we found that Ambra1 binds to multiple classes of proteins in the nucleus, including nuclear pore proteins, adaptor proteins such as FAK and Akap8, chromatin-modifying proteins, and transcriptional regulators like Brg1 and Atf2. We identified biologically important genes, such as Angpt1, Tgfb2, Tgfb3, Itga8, and Itgb7, whose transcription is regulated by Ambra1-scaffolded complexes, likely by altering histone modifications and Atf2 activity. Therefore, in addition to its recognized roles in autophagy and trafficking, Ambra1 scaffolds protein complexes at chromatin, regulating transcriptional signaling in the nucleus. This novel function for Ambra1, and the specific genes impacted, may help to explain the wider role of Ambra1 in cancer cell biology.

中文翻译：

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自噬蛋白 Ambra1 通过支持新型转录复合物来调节基因表达。


Ambra1 被认为是一种自噬和运输蛋白，在神经发生和癌细胞侵袭中发挥作用。在这里，我们报告 Ambra1 也定位于癌细胞的细胞核，在那里它具有控制基因表达的新型核支架功能。利用生化分级分离和蛋白质组学，我们发现 Ambra1 与细胞核中的多类蛋白质结合，包括核孔蛋白、接头蛋白（如 FAK 和 Akap8）、染色质修饰蛋白以及转录调节蛋白（如 Brg1 和 Atf2）。我们鉴定了生物学上重要的基因，例如 Angpt1、Tgfb2、Tgfb3、Itga8 和 Itgb7，其转录受 Ambra1 支架复合物调节，可能是通过改变组蛋白修饰和 Atf2 活性来调节。因此，除了其在自噬和运输中公认的作用外，Ambra1 还在染色质处支撑蛋白质复合物，调节细胞核中的转录信号传导。 Ambra1 的这种新功能以及受影响的特定基因可能有助于解释 Ambra1 在癌细胞生物学中的更广泛作用。