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ATG8 localization in apicomplexan parasites: apicoplast and more?

Mizushima N, Sahani MH - Autophagy (2014)

Bottom Line: In contrast to this established localization, it remains unclear whether these parasites can induce canonical macroautophagy and if ATG8 localizes to autophagosomes.Furthermore, the molecular function of ATG8 in its novel workplace, the apicoplast, is totally unknown.Here, we review recent studies on ATG8 in Plasmodium and Toxoplasma, summarize both consensus and controversial findings, and discuss its potential role in these parasites.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology; Graduate School and Faculty of Medicine; University of Tokyo; Tokyo, Japan.

ABSTRACT
The ATG genes are highly conserved in eukaryotes including yeasts, plants, and mammals. However, these genes appear to be only partially present in most protists. Recent studies demonstrated that, in the apicomplexan parasites Plasmodium (malaria parasites) and Toxoplasma, ATG8 localizes to the apicoplast, a unique nonphotosynthetic plastid with 4 limiting membranes. In contrast to this established localization, it remains unclear whether these parasites can induce canonical macroautophagy and if ATG8 localizes to autophagosomes. Furthermore, the molecular function of ATG8 in its novel workplace, the apicoplast, is totally unknown. Here, we review recent studies on ATG8 in Plasmodium and Toxoplasma, summarize both consensus and controversial findings, and discuss its potential role in these parasites.

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Related in: MedlinePlus

Figure 1. General model of the ATG8 and ATG12 conjugation systems. (A) The ATG8 conjugation system. Immediately after synthesis, the C-terminal extension of ATG8 is cleaved by ATG4 to expose a glycine residue, which is important for the subsequent reaction. After this processing, ATG8 is activated by the E1-like enzyme ATG7 in an ATP-dependent manner and forms a thioester bond between the C-terminal glycine of ATG8 and the active site cysteine of ATG7. Then, ATG8 is transferred to the E2-like enzyme ATG3. ATG8 is finally conjugated with phosphatidylethanolamine (PE). On autophagosomes or autolysosomes, ATG8–PE is deconjugated by ATG4. This system is highly conserved in apicomplexan parasites, but ATG8 in Plasmodium and Toxoplasma lacks the C-terminal extension sequence (shown in gray) and the glycine residue is already exposed without ATG4-mediated processing. (B) The ATG12 conjugation system. ATG12 has a C-terminal glycine and is activated by ATG7 as in the ATG8 system. Then, ATG12 is transferred to ATG10, another E2-like enzyme specific for ATG12, and finally conjugated to a lysine residue of ATG5 via an isopeptide bond. Although the ATG12 system is highly conserved in almost all eukaryotes, ATG10-like proteins have not been clearly identified in apicomplexan parasites. Potential ATG12 (but lacking the C-terminal glycine) and ATG5 proteins can be found in these organisms.
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Figure 1: Figure 1. General model of the ATG8 and ATG12 conjugation systems. (A) The ATG8 conjugation system. Immediately after synthesis, the C-terminal extension of ATG8 is cleaved by ATG4 to expose a glycine residue, which is important for the subsequent reaction. After this processing, ATG8 is activated by the E1-like enzyme ATG7 in an ATP-dependent manner and forms a thioester bond between the C-terminal glycine of ATG8 and the active site cysteine of ATG7. Then, ATG8 is transferred to the E2-like enzyme ATG3. ATG8 is finally conjugated with phosphatidylethanolamine (PE). On autophagosomes or autolysosomes, ATG8–PE is deconjugated by ATG4. This system is highly conserved in apicomplexan parasites, but ATG8 in Plasmodium and Toxoplasma lacks the C-terminal extension sequence (shown in gray) and the glycine residue is already exposed without ATG4-mediated processing. (B) The ATG12 conjugation system. ATG12 has a C-terminal glycine and is activated by ATG7 as in the ATG8 system. Then, ATG12 is transferred to ATG10, another E2-like enzyme specific for ATG12, and finally conjugated to a lysine residue of ATG5 via an isopeptide bond. Although the ATG12 system is highly conserved in almost all eukaryotes, ATG10-like proteins have not been clearly identified in apicomplexan parasites. Potential ATG12 (but lacking the C-terminal glycine) and ATG5 proteins can be found in these organisms.

Mentions: Autophagosome formation requires autophagy-related (Atg) proteins, which were originally identified in the yeast Saccharomyces cerevisiae.2,7 These Atg proteins function as distinct complexes in a hierarchical order.8 The Atg1-Atg13-Atg17-Atg31-Atg29 complex and Atg9-containing vesicles are required for initiation steps. Next, the phosphatidylinositol (PtdIns) 3-kinase complex (Vps30/Atg6-Atg14-Vps15-Vps34) produces PtdIns3P, which recruits the Atg2-Atg18 complex. Finally, the Atg12–Atg5-Atg16 complex and the Atg8– phosphatidylethanolamine (PE) conjugate are required for elongation of the phagophore membrane or completion of closure of the autophagosome (Fig. 1A). These Atg proteins are highly conserved in eukaryotes.9


ATG8 localization in apicomplexan parasites: apicoplast and more?

Mizushima N, Sahani MH - Autophagy (2014)

Figure 1. General model of the ATG8 and ATG12 conjugation systems. (A) The ATG8 conjugation system. Immediately after synthesis, the C-terminal extension of ATG8 is cleaved by ATG4 to expose a glycine residue, which is important for the subsequent reaction. After this processing, ATG8 is activated by the E1-like enzyme ATG7 in an ATP-dependent manner and forms a thioester bond between the C-terminal glycine of ATG8 and the active site cysteine of ATG7. Then, ATG8 is transferred to the E2-like enzyme ATG3. ATG8 is finally conjugated with phosphatidylethanolamine (PE). On autophagosomes or autolysosomes, ATG8–PE is deconjugated by ATG4. This system is highly conserved in apicomplexan parasites, but ATG8 in Plasmodium and Toxoplasma lacks the C-terminal extension sequence (shown in gray) and the glycine residue is already exposed without ATG4-mediated processing. (B) The ATG12 conjugation system. ATG12 has a C-terminal glycine and is activated by ATG7 as in the ATG8 system. Then, ATG12 is transferred to ATG10, another E2-like enzyme specific for ATG12, and finally conjugated to a lysine residue of ATG5 via an isopeptide bond. Although the ATG12 system is highly conserved in almost all eukaryotes, ATG10-like proteins have not been clearly identified in apicomplexan parasites. Potential ATG12 (but lacking the C-terminal glycine) and ATG5 proteins can be found in these organisms.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4206529&req=5

Figure 1: Figure 1. General model of the ATG8 and ATG12 conjugation systems. (A) The ATG8 conjugation system. Immediately after synthesis, the C-terminal extension of ATG8 is cleaved by ATG4 to expose a glycine residue, which is important for the subsequent reaction. After this processing, ATG8 is activated by the E1-like enzyme ATG7 in an ATP-dependent manner and forms a thioester bond between the C-terminal glycine of ATG8 and the active site cysteine of ATG7. Then, ATG8 is transferred to the E2-like enzyme ATG3. ATG8 is finally conjugated with phosphatidylethanolamine (PE). On autophagosomes or autolysosomes, ATG8–PE is deconjugated by ATG4. This system is highly conserved in apicomplexan parasites, but ATG8 in Plasmodium and Toxoplasma lacks the C-terminal extension sequence (shown in gray) and the glycine residue is already exposed without ATG4-mediated processing. (B) The ATG12 conjugation system. ATG12 has a C-terminal glycine and is activated by ATG7 as in the ATG8 system. Then, ATG12 is transferred to ATG10, another E2-like enzyme specific for ATG12, and finally conjugated to a lysine residue of ATG5 via an isopeptide bond. Although the ATG12 system is highly conserved in almost all eukaryotes, ATG10-like proteins have not been clearly identified in apicomplexan parasites. Potential ATG12 (but lacking the C-terminal glycine) and ATG5 proteins can be found in these organisms.
Mentions: Autophagosome formation requires autophagy-related (Atg) proteins, which were originally identified in the yeast Saccharomyces cerevisiae.2,7 These Atg proteins function as distinct complexes in a hierarchical order.8 The Atg1-Atg13-Atg17-Atg31-Atg29 complex and Atg9-containing vesicles are required for initiation steps. Next, the phosphatidylinositol (PtdIns) 3-kinase complex (Vps30/Atg6-Atg14-Vps15-Vps34) produces PtdIns3P, which recruits the Atg2-Atg18 complex. Finally, the Atg12–Atg5-Atg16 complex and the Atg8– phosphatidylethanolamine (PE) conjugate are required for elongation of the phagophore membrane or completion of closure of the autophagosome (Fig. 1A). These Atg proteins are highly conserved in eukaryotes.9

Bottom Line: In contrast to this established localization, it remains unclear whether these parasites can induce canonical macroautophagy and if ATG8 localizes to autophagosomes.Furthermore, the molecular function of ATG8 in its novel workplace, the apicoplast, is totally unknown.Here, we review recent studies on ATG8 in Plasmodium and Toxoplasma, summarize both consensus and controversial findings, and discuss its potential role in these parasites.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology; Graduate School and Faculty of Medicine; University of Tokyo; Tokyo, Japan.

ABSTRACT
The ATG genes are highly conserved in eukaryotes including yeasts, plants, and mammals. However, these genes appear to be only partially present in most protists. Recent studies demonstrated that, in the apicomplexan parasites Plasmodium (malaria parasites) and Toxoplasma, ATG8 localizes to the apicoplast, a unique nonphotosynthetic plastid with 4 limiting membranes. In contrast to this established localization, it remains unclear whether these parasites can induce canonical macroautophagy and if ATG8 localizes to autophagosomes. Furthermore, the molecular function of ATG8 in its novel workplace, the apicoplast, is totally unknown. Here, we review recent studies on ATG8 in Plasmodium and Toxoplasma, summarize both consensus and controversial findings, and discuss its potential role in these parasites.

Show MeSH
Related in: MedlinePlus