Figure 1

Evolutionary descent of the vertebrate Ulk1/2-Atg13-FIP200 complex. (A) In the "baker's yeast" species Saccharomyces cerevisiae, the protein kinase Atg1 is found in a large protein complex that comprises Atg13 and Atg17-Atg29-Atg31, once autophagy is initiated. Under starvation conditions, the hypophosphorylated protein Atg13 induces self-association of Atg1, which strongly enhances its kinase activity. S. cerevisiae additionally expresses Atg11, a scaffolding protein that is involved in the fungi-specific Cvt pathway. (B) The closely related "fission yeast" species Saccharomyces pombe expresses Atg1 and Atg13. Both proteins are essential for autophagy induction [79]. It additionally possesses a homolog of yeast Atg17 and a putative homolog of yeast Atg11 (Taz1IF1) [51, 78]. However, Taz1IF1 shows great similarity to vertebrate FIP200 [51]. The protein Mug66 has been assigned as a putative homolog of vertebrate Atg101 [51]. The molecular details of autophagy induction have not been addressed yet. (C) The nematode Caenorhabditis elegans expresses an Atg1 homolog (UNC-51) and an interacting Atg13 homolog (EPG-1) that both are essential for autophagy induction [24, 32], while the phosphorylation of EPG-1 by UNC-51 has not been determined yet. The nematode genome contains a homolog of both FIP200 (T08A9.1; assigned as atg-11) and Atg101 (Y69A2AR.7); their role in autophagy has not been addressed. (D) In the fruit fly species Drosophila melanogaster, dAtg1 binds and phosphorylates dAtg13. In contrast to yeast, the dAtg1-dependent phosphorylation of Atg13 is greatest under autophagic condition. The composition of the dAtg1-dAtg13 complex is not affected by the nutrient status [34, 35, 37]. The Drosophila genome contains a FIP200 homolog (CG1347) and an Atg101 homolog (CG7053). The involvement of the respective gene products has not been addressed. (E) Vertebrate species possess a large protein complex, comprising Ulk1 or Ulk2, Atg13, FIP200 and Atg101, whose composition is unaffected by the nutrient status [53–56, 68, 75, 76, 85]. In mammals, mTORC1 associates with this complex under normal growth conditions and phosphorylates Ulk1/2 and Atg13, thereby inhibiting Ulk1/2 kinase activity [55]. Active Ulk1/2 autophosphorylates and is able to phosphorylate both Atg13 and FIP200, but the relevance for autophagy induction has not been determined yet.