Phagophore-derived autophagosomes deliver cytoplasmic material to lysosomes for degradation
and reuse. Autophagy mediated by the incompletely characterized actions of Atg proteins
is involved in numerous physiological and pathological settings including stress resistance,
immunity, aging, cancer, and neurodegenerative diseases. Here we characterized Atg17/FIP200,
the Drosophila ortholog of mammalian RB1CC1/FIP200, a proposed functional equivalent
of yeast Atg17. Atg17 disruption inhibits basal, starvation-induced and developmental
autophagy, and interferes with the programmed elimination of larval salivary glands
and midgut during metamorphosis. Upon starvation, Atg17-positive structures appear
at aggregates of the selective cargo Ref(2)P/p62 near lysosomes. This location may
be similar to the perivacuolar PAS (phagophore assembly site) described in yeast.
Drosophila Atg17 is a member of the Atg1 kinase complex as in mammals, and we showed
that it binds to the other subunits including Atg1, Atg13 and Atg101 (C12orf44 in
humans, 9430023L20Rik in mice and RGD1359310 in rats). Atg17 is required for the kinase
activity of endogenous Atg1 in vivo, as loss of Atg17 prevents the Atg1-dependent
shift of endogenous Atg13 to hyperphosphorylated forms, and also blocks punctate Atg1
localization during starvation. Finally, we found that Atg1 overexpression induces
autophagy and reduces cell size in Atg17-null mutant fat body cells, and that overexpression
of Atg17 promotes endogenous Atg13 phosphorylation and enhances autophagy in an Atg1-dependent
manner in the fat body. We propose a model according to which the relative activity
of Atg1, estimated by the ratio of hyper- to hypophosphorylated Atg13, contributes
to setting low (basal) vs. high (starvation-induced) autophagy levels in Drosophila.
