Autophagy proteins regulate ERK phosphorylation.
Autophagy is a conserved pathway that maintains cellular quality control. Extracellular signal-regulated kinase (ERK) controls various aspects of cell physiology including proliferation. Multiple signalling cascades, including ERK, have been shown to regulate autophagy, however whether autophagy proteins (ATG) regulate cell signalling is unknown. Here we show that growth factor exposure increases the interaction of ERK cascade components with ATG proteins in the cytosol and nucleus. ERK and its upstream kinase MEK localize to the extra-luminal face of autophagosomes. ERK2 interacts with ATG proteins via its substrate-binding domains. Deleting Atg7 or Atg5 or blocking LC3 lipidation or ATG5-ATG12 conjugation decreases ERK phosphorylation. Conversely, increasing LC3-II availability by silencing the cysteine protease ATG4B or acute trehalose exposure increases ERK phosphorylation. Decreased ERK phosphorylation in Atg5⁻/⁻ cells does not occur from overactive phosphatases. Our findings thus reveal an unconventional function of ATG proteins as cellular scaffolds in the regulation of ERK phosphorylation.
1] Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA [2] Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Nuria
N
Martinez-Lopez
Diana
D
Athonvarangkul
Priti
P
Mishall
Srabani
S
Sahu
Rajat
R
Singh
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation
C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C582881:Atg4b protein, mouse; D003546:Cysteine Endopeptidases; D000071193:Autophagy-Related Protein 7