Abstract
The biogenesis of autophagosomes depends on the conjugation of Atg8-like proteins with phosphatidylethanolamine. Atg8 processing by the cysteine protease Atg4 is required for its covalent linkage to phosphatidylethanolamine, but it is also necessary for Atg8 deconjugation from this lipid to release it from membranes. How these two cleavage steps are coordinated is unknown. Here we show that phosphorylation by Atg1 inhibits Atg4 function, an event that appears to exclusively occur at the site of autophagosome biogenesis. These results are consistent with a model where the Atg8-phosphatidylethanolamine pool essential for autophagosome formation is protected at least in part by Atg4 phosphorylation by Atg1 while newly synthesized cytoplasmic Atg8 remains susceptible to constitutive Atg4 processing.
Highlights
The biogenesis of autophagosomes depends on the conjugation of Atg8-like proteins with phosphatidylethanolamine
Previous studies suggest that sealed autophagosomes cannot fuse with lysosomes/vacuoles until the Atg proteins get dissociated from autophagosomal membranes[4], which partially depends on phosphatidylinositol-3-phosphate (PI3P) turnover[5, 6]
The Atg[1] kinase fits with this profile, because it dynamically localizes to the PAS17, and it has been shown that its phosphorylations can be antagonized by phosphatases[18]
Summary
The biogenesis of autophagosomes depends on the conjugation of Atg8-like proteins with phosphatidylethanolamine. Atg[8] processing by the cysteine protease Atg[4] is required for its covalent linkage to phosphatidylethanolamine, but it is necessary for Atg[8] deconjugation from this lipid to release it from membranes. We show that phosphorylation by Atg[1] inhibits Atg[4] function, an event that appears to exclusively occur at the site of autophagosome biogenesis These results are consistent with a model where the Atg8-phosphatidylethanolamine pool essential for autophagosome formation is protected at least in part by Atg[4] phosphorylation by Atg[1] while newly synthesized cytoplasmic Atg[8] remains susceptible to constitutive Atg[4] processing. We describe a novel regulatory mechanism, in which the Atg[1] kinase inhibits the deconjugating activity of Atg[4] at the PAS, possibly contributing to the protection of the Atg8–PE pool necessary for autophagosome biogenesis
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