AMBRA1

Enables enzyme binding activity; protein phosphatase activator activity; and ubiquitin-like ligase-substrate adaptor activity. Involved in several processes, including macroautophagy; positive regulation of free ubiquitin chain polymerization; and positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction. Located in cytosol. Part of Cul4-RING E3 ubiquitin ligase complex. Is active in cytoskeleton; mitochondrion; and nucleus. Biomarker of multiple system atrophy.

autophagy and beclin 1 regulator 1

Neuroscience,Cardiovascular

Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex involved in cell cycle control and autophagy (PubMed:20921139, PubMed:23524951, PubMed:24587252, PubMed:32333458, PubMed:33854232, PubMed:33854235, PubMed:33854239).
The DCX(AMBRA1) complex specifically mediates the polyubiquitination of target proteins such as BECN1, CCND1, CCND2, CCND3, ELOC and ULK1 (PubMed:23524951, PubMed:33854232, PubMed:33854235, PubMed:33854239).
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 (PubMed:33854232, PubMed:33854235, PubMed:33854239).
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 (PubMed:33854232, PubMed:33854235, PubMed:33854239).
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 (PubMed:25438055, PubMed:25803737).
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 (PubMed:25499913, PubMed:30166453).
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 (PubMed:21358617).
In normal conditions, AMBRA1 is tethered to the cytoskeleton via interaction with dyneins DYNLL1 and DYNLL2 (PubMed:20921139).
Upon autophagy induction, AMBRA1 is released from the cytoskeletal docking site to induce autophagosome nucleation by mediating ubiquitination of proteins involved in autophagy (PubMed:20921139).
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 (PubMed:23524951).
Also activates ULK1 via interaction with TRIM32: TRIM32 stimulates ULK1 through unanchored 'Lys-63'-linked polyubiquitin chains (PubMed:31123703).
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 (PubMed:21753002, PubMed:25215947).
Also activates mitophagy by acting as a cofactor for HUWE1; acts by promoting HUWE1-mediated ubiquitination of MFN2 (PubMed:30217973).
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 (PubMed:30513302).
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).

Autophagosome assembly Source: ParkinsonsUK-UCL
Autophagy Source: GO_Central
Autophagy of mitochondrion Source: ParkinsonsUK-UCL
Cell differentiation Source: UniProtKB-KW
Cellular response to starvation Source: Ensembl
Macroautophagy Source: Reactome
Mitophagy Source: ParkinsonsUK-UCL
Negative regulation of cardiac muscle cell apoptotic process Source: Ensembl
Negative regulation of cell population proliferation Source: Ensembl
Negative regulation of neuron apoptotic process Source: Ensembl
Neural tube development Source: Ensembl
Positive regulation of autophagy Source: Ensembl
Positive regulation of phosphatidylinositol 3-kinase activity Source: ParkinsonsUK-UCL
Response to mitochondrial depolarisation Source: ParkinsonsUK-UCL

Endoplasmic reticulum
Cytoplasm, cytoskeleton
Cytoplasmic vesicle, autophagosome
Mitochondrion
Cytoplasm, cytosol
Nucleus
Cell junction, focal adhesion

Phosphorylation at Ser-52 by MTOR inhibits its ability to regulate autophagy and mediate ubiquitination of ULK1 (PubMed:23524951).
Phosphorylation by ULK1 in response to autophagy induction abolishes interaction with DYNLL1 and DYNLL2, releasing AMBRA1 from the cytoskeletal docking site to induce autophagosome nucleation (PubMed:20921139).
Phosphorylation by MTOR inhibits interaction with PPP2CA and subsequent dephosphorylation of MYC (PubMed:25438055).
Phosphorylation at Ser-1043 by CHUK/IKKA promotes its interaction with ATG8 family proteins GABARAP and MAP1LC3B and its mitophagic activity (PubMed:30217973).
Ubiquitinated by RNF2 via 'Lys-48'-linkage in unstressed cells, leading to its degradation by the proteasome (PubMed:25499913).
Induction of autophagy promotes stabilization via interaction with CUL4 (CUL4A or CUL4B) and DDB1 (PubMed:25499913).
Upon prolonged starvation, ubiquitinated and degraded, terminating the autophagy response (PubMed:25499913).
Undergoes proteolytic processing by caspase-6 (CASP6), caspase-7 (CASP7) and caspase-8 (CASP8) during apoptosis, resulting in the dismantling of the autophagic machinery and the accomplishment of the programmed cell death program (PubMed:22441670).
Also cleaved by calpains during apoptosis, which mediate a complete proteolytic degradation (PubMed:22441670).