The autophagy protein Ambra1 regulates gene expression by supporting novel transcriptional complexes

Christina Schoenherr, Adam Byron, Billie G. C. Griffith, Alexander E. P. Loftus, Jimi C. Wills, Alison F. Munro, Alex von Kriegsheim, Margaret C. Frame

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)12045-12057
Number of pages13
JournalJournal of Biological Chemistry
Volume295
Issue number34
DOIs
Publication statusPublished - 21 Aug 2020

Keywords

  • Ambra1
  • trafficking
  • autophagy
  • nucleus
  • transcription
  • Atf2
  • chromatin
  • Akap8
  • Cdk9
  • DNA transcription

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