|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
|
Fig. 3. Evolutionary conservation of the molecular machinery of autophagy.
The initial formation of the autophagosome can be divided into distinct steps:
(A) induction, (B) vesicle nucleation and (C) vesicle elongation. (A)
In yeast, Tor controls the phosphorylation (P) state of Atg13, a protein
required for autophagy. Inhibition of Tor causes the dephosphorylation of
Atg13 and the subsequent formation of a complex containing Atg1, Atg13, Atg17
and several other proteins, which in turn induces autophagy. Orthologs of
Atg13 and Atg1 have been identified in metazoans, but no ortholog to Atg17 has
been identified. In metazoans, Tor similarly inhibits autophagy, but whether
this is through an interaction between Atg1 and Atg13 or an equivalent protein
to Atg17 is not known. (B) The vesicle nucleation step (the formation
of the isolation membrane/phagophore) results from the activity of a
phosphatidylinositol 3 kinase (PI3K/Vps34) complex, which localizes other
pre-autophagosomal proteins to the phagophore. In mammals, Bcl2, Uvrag and
Bif1 are part of this complex. Orthologs to all three proteins exist in
Drosophila and C. elegans. (C) The vesicle expansion
of the phagophore into an autophagosome results from the concerted action of
two novel and highly conserved ubiquitin-like conjugation pathways, the Atg12
conjugation system (Atg12p, Atg5p and Atg16p), and the Atg8 lipidation system
(Atg8, Atg3 and Atg7). These pathways function in mice; however, it is not
known whether the same multimeric structures occur in all metazoans. E1,
E1-like ubiquitin activating enzyme; E2, E2-like ubiquitin conjugating enzyme;
G, glycine of Atg8; PE, phosphatidylethanolamine that gets covalently linked
to Atg8.
|
