Activating molecule in BECN1-regulated autophagy protein 1

Definition:

Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex involved in cell cycle control and autophagy. The DCX(AMBRA1) complex specifically mediates the polyubiquitination of target proteins such as BECN1, CCND1, CCND2, CCND3, ELOC and ULK1. Acts as an upstream master regulator of the transition from G1 to S cell phase: AMBRA1 specifically recognizes and binds phosphorylated cyclin-D (CCND1, CCND2 and CCND3), leading to cyclin-D ubiquitination by the DCX(AMBRA1) complex and subsequent degradation. By controlling the transition from G1 to S phase and cyclin-D degradation, AMBRA1 acts as a tumor suppressor that promotes genomic integrity during DNA replication and counteracts developmental abnormalities and tumor growth. AMBRA1 also regulates the cell cycle by promoting MYC dephosphorylation and degradation independently of the DCX(AMBRA1) complex: acts via interaction with the catalytic subunit of protein phosphatase 2A (PPP2CA), which enhances interaction between PPP2CA and MYC, leading to MYC dephosphorylation and degradation. Acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating ubiquitination and degradation of Elongin-C (ELOC) component of CRL5 complexes. Acts as a key regulator of autophagy by modulating the BECN1-PIK3C3 complex: controls protein turnover during neuronal development, and regulates normal cell survival and proliferation. In normal conditions, AMBRA1 is tethered to the cytoskeleton via interaction with dyneins DYNLL1 and DYNLL2. Upon autophagy induction, AMBRA1 is released from the cytoskeletal docking site to induce autophagosome nucleation by mediating ubiquitination of proteins involved in autophagy. The DCX(AMBRA1) complex mediates 'Lys-63'-linked ubiquitination of BECN1, increasing the association between BECN1 and PIK3C3 to promote PIK3C3 activity (By similarity). In collaboration with TRAF6, AMBRA1 mediates 'Lys-63'-linked ubiquitination of ULK1 following autophagy induction, promoting ULK1 stability and kinase activity. Also activates ULK1 via interaction with TRIM32: TRIM32 stimulates ULK1 through unanchored 'Lys-63'-linked polyubiquitin chains. Also acts as an activator of mitophagy via interaction with PRKN and LC3 proteins (MAP1LC3A, MAP1LC3B or MAP1LC3C); possibly by bringing damaged mitochondria onto autophagosomes. Also activates mitophagy by acting as a cofactor for HUWE1; acts by promoting HUWE1-mediated ubiquitination of MFN2. AMBRA1 is also involved in regulatory T-cells (Treg) differentiation by promoting FOXO3 dephosphorylation independently of the DCX(AMBRA1) complex: acts via interaction with PPP2CA, which enhances interaction between PPP2CA and FOXO3, leading to FOXO3 dephosphorylation and stabilization. May act as a regulator of intracellular trafficking, regulating the localization of active PTK2/FAK and SRC (By similarity). Also involved in transcription regulation by acting as a scaffold for protein complexes at chromatin (By similarity).

References:

[1]. Daniele Simoneschi, et al. CRL4AMBRA1 is a master regulator of D-type cyclins. Nature. 2021 Apr;592(7856):789-793. [Content Brief]

[2]. Flavie Strappazzon, et al. Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy. EMBO J. 2011 Apr 6;30(7):1195-208. [Content Brief]

[3]. Cindy Van Humbeeck, et al. Parkin interacts with Ambra1 to induce mitophagy. J Neurosci. 2011 Jul 13;31(28):10249-61. [Content Brief]

[4]. Andrea C Chaikovsky, et al. The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D. Nature. 2021 Apr;592(7856):794-798. [Content Brief]

[5]. Emiliano Maiani, et al. AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity. Nature. 2021 Apr;592(7856):799-803. [Content Brief]

[6]. Manuela Antonioli, et al. AMBRA1 interplay with cullin E3 ubiquitin ligases regulates autophagy dynamics. Dev Cell. 2014 Dec 22;31(6):734-46. [Content Brief]

[7]. Si-Han Chen, et al. CRL4AMBRA1 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling. EMBO J. 2018 Sep 14;37(18):e97508. [Content Brief]

[8]. Valentina Cianfanelli, et al. AMBRA1 and BECLIN 1 interplay in the crosstalk between autophagy and cell proliferation. Cell Cycle. 2015;14(7):959-63. [Content Brief]

[9]. F Strappazzon, et al. AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1. Cell Death Differ. 2015 Mar;22(3):419-32. [Content Brief]

[10]. Jianhong Ye, et al. Rare mutations in the autophagy-regulating gene AMBRA1 contribute to human neural tube defects. Hum Mutat. 2020 Aug;41(8):1383-1393. [Content Brief]

[11]. Wen Gu, et al. Ambra1 is an essential regulator of autophagy and apoptosis in SW620 cells: pro-survival role of Ambra1. PLoS One. 2014 Feb 26;9(2):e90151. [Content Brief]

[12]. Anthea Di Rita, et al. HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα. Nat Commun. 2018 Sep 14;9(1):3755. [Content Brief]

[13]. Juliane Becher, et al. AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis. Dev Cell. 2018 Dec 3;47(5):592-607.e6. [Content Brief]

[14]. Sabrina Di Bartolomeo, et al. The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J Cell Biol. 2010 Oct 4;191(1):155-68. [Content Brief]

[15]. Francesca Nazio, et al. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat Cell Biol. 2013 Apr;15(4):406-16. [Content Brief]

[16]. Valentina Cianfanelli, et al. AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. Nat Cell Biol. 2015 Jan;17(1):20-30. [Content Brief]

[17]. M Di Rienzo, et al. Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains. Sci Adv. 2019 May 8;5(5):eaau8857. [Content Brief]

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