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Cell Death Differ. 2016 Dec;23(12):2007-2018. doi: 10.1038/cdd.2016.80. Epub 2016 Sep 30.

Autophagy requires poly(adp-ribosyl)ation-dependent AMPK nuclear export.

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Instituto López Neyra de Parasitología y Biomedicina, IPBLN, CSIC PTS-Granada, Armilla, Spain.
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas, Sevilla, Spain.
Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; MTA-DE Cell Biology and Signaling Research Group, Debrecen, Hungary.
Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, UMR7242, Centre National de la Recherche Scientifique / Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, Boulevard S. Brant, BP10413, 67412 Illkirch, France.


AMPK is a central energy sensor linking extracellular milieu fluctuations with the autophagic machinery. In the current study we uncover that Poly(ADP-ribosyl)ation (PARylation), a post-translational modification (PTM) of proteins, accounts for the spatial and temporal regulation of autophagy by modulating AMPK subcellular localisation and activation. More particularly, we show that the minority AMPK pool needs to be exported to the cytosol in a PARylation-dependent manner for optimal induction of autophagy, including ULK1 phosphorylation and mTORC1 inactivation. PARP-1 forms a molecular complex with AMPK in the nucleus in non-starved cells. In response to nutrient deprivation, PARP-1 catalysed PARylation, induced the dissociation of the PARP-1/AMPK complex and the export of free PARylated nuclear AMPK to the cytoplasm to activate autophagy. PARP inhibition, its silencing or the expression of PARylation-deficient AMPK mutants prevented not only the AMPK nuclear-cytosolic export but also affected the activation of the cytosolic AMPK pool and autophagosome formation. These results demonstrate that PARylation of AMPK is a key early signal to efficiently convey extracellular nutrient perturbations with downstream events needed for the cell to optimize autophagic commitment before autophagosome formation.

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