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

AuthorsRodríguez-Vargas, José Manuel; Rodríguez, María Isabel; Majuelos-Melguizo, Jara; García-Diaz, Ángel; González-Flores, Ariannys; López-Rivas, Abelardo ; Dantzer, Françoise; Oliver, Francisco Javier
Issue Date2016
PublisherNature Publishing Group
CitationCell Death and Differentiation 23(12): 2007-2018 (2016)
AbstractAMPK 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.
DescriptionRodríguez-Vargas, José Manuel et al.
Publisher version (URL)https://doi.org/10.1038/cdd.2016.80
Identifiersdoi: 10.1038/cdd.2016.80
e-issn: 1476-5403
issn: 1350-9047
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