title: Drosophila Gyf/GRB10 interacting GYF protein is an autophagy regulator that controls neuron and muscle homeostasis.
abstract: Autophagy is an essential process for eliminating ubiquitinated protein aggregates and dysfunctional organelles. Defective autophagy is associated with various degenerative diseases such as Parkinson disease. Through a genetic screening in Drosophila, we identified CG11148, whose product is orthologous to GIGYF1 (GRB10-interacting GYF protein 1) and GIGYF2 in mammals, as a new autophagy regulator; we hereafter refer to this gene as Gyf. Silencing of Gyf completely suppressed the effect of Atg1-Atg13 activation in stimulating autophagic flux and inducing autophagic eye degeneration. Although Gyf silencing did not affect Atg1-induced Atg13 phosphorylation or Atg6-Pi3K59F (class III PtdIns3K)-dependent Fyve puncta formation, it inhibited formation of Atg13 puncta, suggesting that Gyf controls autophagy through regulating subcellular localization of the Atg1-Atg13 complex. Gyf silencing also inhibited Atg1-Atg13-induced formation of Atg9 puncta, which is accumulated upon active membrane trafficking into autophagosomes. Gyf-null mutants also exhibited substantial defects in developmental or starvation-induced accumulation of autophagosomes and autolysosomes in the larval fat body. Furthermore, heads and thoraxes from Gyf-null adults exhibited strongly reduced expression of autophagosome-associated Atg8a-II compared to wild-type (WT) tissues. The decrease in Atg8a-II was directly correlated with an increased accumulation of ubiquitinated proteins and dysfunctional mitochondria in neuron and muscle, which together led to severe locomotor defects and early mortality. These results suggest that Gyf-mediated autophagy regulation is important for maintaining neuromuscular homeostasis and preventing degenerative pathologies of the tissues. Since human mutations in the GIGYF2 locus were reported to be associated with a type of familial Parkinson disease, the homeostatic role of Gyf-family proteins is likely to be evolutionarily conserved.
authors.affiliation: a Department of Molecular and Integrative Physiology ; University of Michigan ; Ann Arbor , MI USA.
authors.forename: Myungjin
authors.initials: M
authors.lastname: Kim
authors.forename: Ian
authors.initials: I
authors.lastname: Semple
authors.forename: Boyoung
authors.initials: B
authors.lastname: Kim
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kiers
authors.forename: Samuel
authors.initials: S
authors.lastname: Nam
authors.forename: Hwan-Woo
authors.initials: HW
authors.lastname: Park
authors.forename: Haeli
authors.initials: H
authors.lastname: Park
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Ro
authors.forename: Jeong-Sig
authors.initials: JS
authors.lastname: Kim
authors.forename: Gábor
authors.initials: G
authors.lastname: Juhász
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D001921:Brain / Q000378:metabolism; D004330:Drosophila / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D005260:Female; D051383:GRB10 Adaptor Protein / Q000378:metabolism*; D020868:Gene Silencing; D006706:Homeostasis; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009132:Muscles / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D025801:Ubiquitin / Q000737:chemistry; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: C541704:Atg13 protein, Drosophila; C580769:Atg6 protein, Drosophila; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D029721:Drosophila Proteins; C000608362:Gyf protein, Drosophila; D025801:Ubiquitin; D033921:Vesicular Transport Proteins; D051383:GRB10 Adaptor Protein; C518074:Atg1 protein, Drosophila; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases
keywords: Drosophila; aging; autophagy; growth; neurodegeneration