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

• Published in: The Journal of biological chemistry Vol. 295; no. 34; pp. 12045 - 12057
• Main Authors: Schoenherr, Christina, Byron, Adam, Griffith, Billie, Loftus, Alexander, Wills, Jimi C., Munro, Alison F., von Kriegsheim, Alex, Frame, Margaret C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.08.2020; American Society for Biochemistry and Molecular Biology
• Subjects: A Kinase Anchor Proteins - genetics; A Kinase Anchor Proteins - metabolism; Activating Transcription Factor 2 - genetics; Activating Transcription Factor 2 - metabolism; Active Transport, Cell Nucleus - genetics; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Akap8; Ambra1; Angiopoietin-1 - biosynthesis; Angiopoietin-1 - genetics; Atf2; autophagy; Cdk9; Cell Biology; Cell Line; chromatin; Chromatin - genetics; Chromatin - metabolism; DNA Helicases - genetics; DNA Helicases - metabolism; DNA transcription; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - metabolism; Gene Expression Regulation; Humans; Integrin alpha Chains - biosynthesis; Integrin alpha Chains - genetics; Integrin beta Chains - biosynthesis; Integrin beta Chains - genetics; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; nucleus; Signal Transduction; trafficking; transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Transforming Growth Factor beta2 - biosynthesis; Transforming Growth Factor beta2 - genetics; Transforming Growth Factor beta3 - biosynthesis; Transforming Growth Factor beta3 - genetics; Atf2; Cdk9; autophagy; transcription; Ambra1; nucleus; Akap8; chromatin; trafficking; DNA transcription
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA120.012565

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.