DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy.
Autophagy, an evolutionarily conserved process, has functions both in cytoprotective and programmed cell death mechanisms. Beclin 1, an essential autophagic protein, was recently identified as a BH3-domain-only protein that binds to Bcl-2 anti-apoptotic family members. The dissociation of beclin 1 from its Bcl-2 inhibitors is essential for its autophagic activity, ... and therefore should be tightly controlled. Here, we show that death-associated protein kinase (DAPK) regulates this process. The activated form of DAPK triggers autophagy in a beclin-1-dependent manner. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy. These results reveal a substrate for DAPK that acts as one of the core proteins of the autophagic machinery, and they provide a new phosphorylation-based mechanism that reduces the interaction of beclin 1 with its inhibitors to activate the autophagic machinery.
Mesh Terms:
Animals, Apoptosis Regulatory Proteins, Autophagy, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Death-Associated Protein Kinases, Humans, Membrane Proteins, Models, Molecular, Phosphorylation, Protein Conformation, Recombinant Fusion Proteins, bcl-X Protein
Animals, Apoptosis Regulatory Proteins, Autophagy, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Death-Associated Protein Kinases, Humans, Membrane Proteins, Models, Molecular, Phosphorylation, Protein Conformation, Recombinant Fusion Proteins, bcl-X Protein
EMBO Rep.
Date: Mar. 01, 2009
PubMed ID: 19180116
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