Autophagy requires poly(adp-ribosyl)ation-dependent AMPK nuclear export.
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.
Instituto López Neyra de Parasitología y Biomedicina, IPBLN, CSIC PTS-Granada, Armilla, Spain.
José M
JM
Rodríguez-Vargas
Instituto López Neyra de Parasitología y Biomedicina, IPBLN, CSIC PTS-Granada, Armilla, Spain.
María I
MI
Rodríguez
Instituto López Neyra de Parasitología y Biomedicina, IPBLN, CSIC PTS-Granada, Armilla, Spain.
Jara
J
Majuelos-Melguizo
Instituto López Neyra de Parasitología y Biomedicina, IPBLN, CSIC PTS-Granada, Armilla, Spain.
Ángel
Á
García-Diaz
Instituto López Neyra de Parasitología y Biomedicina, IPBLN, CSIC PTS-Granada, Armilla, Spain.
Ariannys
A
González-Flores
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas, Sevilla, Spain.
Abelardo
A
López-Rivas
Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; MTA-DE Cell Biology and Signaling Research Group, Debrecen, Hungary.
László
L
Virág
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.
Giuditta
G
Illuzzi
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.
Valerie
V
Schreiber
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.
Françoise
F
Dantzer
Instituto López Neyra de Parasitología y Biomedicina, IPBLN, CSIC PTS-Granada, Armilla, Spain.
F Javier
FJ
Oliver
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000263:Adenylate Kinase / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D001343:Autophagy / Q000187:drug effects; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D008954:Models, Biological; D000074747:Poly ADP Ribosylation / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D047908:Intracellular Signaling Peptides and Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D000071189:Autophagy-Related Protein-1 Homolog; D000076222:Mechanistic Target of Rapamycin Complex 1; C484754:ULK1 protein, human; D000263:Adenylate Kinase
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