The Atg12-Atg5 Conjugate Has a Novel E3-like Activity for Protein Lipidation in Autophagy*

By T. Hanada, N. Noda, Y. Satomi, Yoshinobu Ichimura, Y. Fujioka, Toshifumi Takao, F. Inagaki, Y. Ohsumi. Journal of Biological Chemistry, 2007

1,119 citations recorded by the source corpus.

Autophagy is a bulk degradation process in eukaryotic cells; autophagosomes enclose cytoplasmic components for degradation in the lysosome/vacuole. Autophagosome formation requires two ubiquitin-like conjugation systems, the Atg12 and Atg8 systems, which are tightly associated with expansion of autophagosomal membrane. Previous studies have suggested that there is a hierarchy between these systems; the Atg12 system is located upstream of the Atg8 system in the context of Atg protein organization. However, the concrete molecular relationship is unclear. Here, we show using an in vitro Atg8 conjugation system that the Atg12-Atg5 conjugate, but not unconjugated Atg12 or Atg5, strongly enhances the formation of the other conjugate, Atg8-PE. The Atg12-Atg5 conjugate promotes the transfer of Atg8 from Atg3 to the substrate, phosphatidylethanolamine (PE), by stimulating the activity of Atg3. We also show that the Atg12-Atg5 conjugate interacts with both Atg3 and PE-containing liposomes. These results indicate that the Atg12-Atg5 conjugate is a ubiquitin-protein ligase (E3)-like enzyme for Atg8-PE conjugation reaction, distinctively promoting protein-lipid conjugation.

Subfields: Epidemiology, Parasitology, Physiology

View Paper: https://www.semanticscholar.org/paper/ac42037b48b9d80a5e5c15efd2379440ed23b91c

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Citations in the corpus

Regulation Mechanisms and Signaling Pathways of Autophagy (2009, background): “Atg8 is finally conjugated to the target lipid PE via an amide bond, facilitated by the E3like Atg12–Atg5 conjugate (32,37), although Atg12–Atg5 lacks the conserved HECT or RING domains possessed by typical E3 ligases, and is not essential for conjugation to occur.”
Mechanisms of Selective Autophagy (2016, positive): “The reaction proceeds similarly to the conjugation of ubiquitin to lysine residues in target proteins and requires Atg7 as the activating enzyme (E1), Atg3 as the conjugating enzyme (E2) and the Atg12 – Atg5 – Atg16 protein complex as the E3-like enzyme [73,75,76].”
Dynamics and diversity in autophagy mechanisms: lessons from yeast (2009, background): “It has also been shown that purified Atg12–Atg5 conjugates drastically stimulate the formation of Atg8–PE in vitro”
Autophagy, Immunity, and Microbial Adaptations (2009, background): “…conjugate that associates noncovalently with Atg16L1 (the mammalian equivalent of yeast Atg16) to form a putative E3 enzyme (terminology borrowed from the ubiquitin system) (Hanada et al., 2007), directing the site of the formation of the second protein-lipid conjugate (Fujita et al., 2008).”
LC3 and GATE‐16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis (2010, background): “Moreover, the Atg12–Atg5 conjugate may act as an E3-like enzyme for the conjugation of Atg8s to PE and, together with Atg16, is responsible for their recruit- ment to the phagophore (Hanada et al, 2007; Fujita et al, 2008b).”
Autophagy-Dependent Ferroptosis: Machinery and Regulation (2020, background): “The first system involves the ATG12-ATG5ATG16L1 pathway (Hanada et al., 2007).”
The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. (2008, background): “There is a physical interaction between Atg12 and Atg3 in both yeast and mammals (Uetz et al., 2000; Tanida et al., 2002; Hanada et al., 2007); however, the functional significance of this interaction has not been fully elucidated.”
Atg8 controls phagophore expansion during autophagosome formation. (2008, background): “A multimeric protein complex formed by Atg12, Atg5, and Atg16 facilitates the conjugation of Atg8, possibly by serving as an E3-like enzyme (Suzuki et al., 2001; Hanada et al., 2007).”
Cell Death Signaling. (2015, background): “The ATG5-ATG12-ATG16L complex then acts as an E3 ligase, conjugating LC3 to phosphatidylethanolamine (PE) to form an LC3-PE conjugate (also referred to as LC3-II) (Hanada et al. 2007).”
An Overview of the Molecular Mechanism of Autophagy (2009, background): “6), although it is not essential for the latter process to occur (Hanada et al. 2007).”