title: Metabolic-stress-induced rearrangement of the 14-3-3ζ interactome promotes autophagy via a ULK1- and AMPK-regulated 14-3-3ζ interaction with phosphorylated Atg9.
abstract: 14-3-3ζ promotes cell survival via dynamic interactions with a vast network of binding partners, many of which are involved in stress regulation. We show here that hypoxia (low glucose and oxygen) triggers a rearrangement of the 14-3-3ζ interactome to favor an interaction with the core autophagy regulator Atg9A. Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK. However, upon induction of hypoxic stress, activated AMPK bypasses the requirement for ULK1 and mediates S761 phosphorylation directly, resulting in an increase in 14-3-3ζ interactions, recruitment of Atg9A to LC3-positive autophagosomes, and enhanced autophagosome production. These data suggest a novel mechanism whereby the level of autophagy induction can be modulated by AMPK/ULK1-mediated phosphorylation of mammalian Atg9A.
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA.
authors.forename: Vajira K
authors.initials: VK
authors.lastname: Weerasekara
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Panek
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Broadbent
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Mortenson
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mathis
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA.
authors.forename: Gideon N
authors.initials: GN
authors.lastname: Logan
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Prince
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Thomson
authors.affiliation: Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: J Will
authors.initials: JW
authors.lastname: Thompson
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA jandersen@chem.byu.edu.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Andersen
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics* / Q000378:metabolism*; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D000071183:Autophagy-Related Proteins; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013312:Stress, Physiological; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; C574794:ATG9A protein, human; D000071183:Autophagy-Related Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; C572235:YWHAZ protein, human; D012694:Serine; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; D055372:AMP-Activated Protein Kinases