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9.A.15 The Autophagy-related Phagophore-formation Transporter (APT) Family

Autophagy is the degradation of a cell's own components within lysosomes (or the analogous yeast vacuole), and its malfunction contributes to a variety of human diseases. Atg9 is the sole integral membrane protein required in formation of the initial sequestering compartment, the phagophore, and is proposed to play a key role in membrane transport; the phagophore presumably expands by vesicular addition to form a complete autophagosome. It is not clear through what mechanism Atg9 functions at the phagophore assembly site (PAS) (Munakata and Klionsky, 2010). He et al. (2008) reported that Atg9 molecules self-associate independently of other known autophagy proteins in both nutrient-rich and starvation conditions. Mutational analyses revealed that self-interaction is critical for anterograde transport of Atg9 to the PAS. The ability of Atg9 to self-interact is required for both selective and nonselective autophagy at the step of phagophore expansion at the PAS. Atg9 multimerization facilitates membrane flow to the PAS for phagophore formation. It includes 6 putative TMSs. 

Eukaryotic cells employ autophagy to degrade damaged or obsolete organelles and proteins (Umemiya et al., 2007). Central to this process is the formation of autophagosomes, double-membrane vesicles responsible for delivering cytoplasmic material to lysosomes. In the past decade many autophagy-related genes, Atg, have been identified that are required for autophagic functions. In all types of autophagy, a core molecular machinery has a critical role in forming sequestering vesicles, the autophagosome, which is the hallmark morphological feature of this dynamic process. Additional components allow autophagy to adapt to the changing needs of the cell (Xie and Klionsky, 2007).

In yeast, approximately 31 autophagy-related (Atg) proteins have been identified. Most of them reside at the phagophore assembly site (PAS). Geng et al. (2008) reported the application of fluorescence microscopy to study the amount of Atg proteins at the PAS. They found that an increase in the amount of Atg11 at the PAS enhanced the recruitment of Atg8 and Atg9 to this site and facilitated the formation of more cytoplasm-to-vacuole targeting vesicles. In response to autophagy induction, the amount of most Atg proteins remained unchanged at the PAS, whereas an enhanced recruitment of Atg8 and 9 at this site was observed. During autophagy, the amount of Atg8 at the PAS showed a periodic change, indicating the formation of autophagosomes, and both Atg8 and Atg12 were ubiquitinylated (Geng and Klionsky, 2008). Novel Atg proteins and the stages of their action have been identified (Backues et al. 2015).

Atg9 is the only characterized transmembrane protein that is absolutely required for Cvt vesicle formation, and it is proposed to carry membrane from peripheral donor sites to the phagophore assembly site where the vesicle forms. Additional proteins, including Atg11, Atg23, and Atg27, are involved in this anterograde movement, whereas Atg1-Atg13 and Atg2-Atg18 are required for the retrograde return to the peripheral sites (Munakata and Klionsky, 2010). Atg11 and Atg23 show low sequence similarity to MLP1 and MLP2 of the Nuclear Pore Complex (NPC; 1.A.75.1.1). These proteins include repeat sequences. Atg1 is a serine, thereonine protein kinase; also called autophagy protein 3 or cytoplasm to vacuole targeting protein 10.

The table (Table 3) presented below is taken from (Munakata and Klionsky 2010).

This family belongs to the: Protein Kinase (PK) Superfamily.

References associated with 9.A.15 family:

Backues, S.K., D.P. Orban, A. Bernard, K. Singh, Y. Cao, and D.J. Klionsky. (2015). Atg23 and Atg27 act at the early stages of Atg9 trafficking in S. cerevisiae. Traffic 16: 172-190. 25385507
Feng, Y., S.K. Backues, M. Baba, J.M. Heo, J.W. Harper, and D.J. Klionsky. (2016). Phosphorylation of Atg9 regulates movement to the phagophore assembly site and the rate of autophagosome formation. Autophagy 12: 648-658. 27050455
Geng, J. and D.J. Klionsky. (2008). The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. 'Protein modifications: beyond the usual suspects' review series. EMBO Rep 9: 859-864. 18704115
Geng, J., M. Baba, U. Nair, and D.J. Klionsky. (2008). Quantitative analysis of autophagy-related protein stoichiometry by fluorescence microscopy. J. Cell Biol. 182: 129-140. 18625846
He, C., M. Baba, Y. Cao, and D.J. Klionsky. (2008). Self-interaction is critical for Atg9 transport and function at the phagophore assembly site during autophagy. Mol. Biol. Cell 19: 5506-5516. 18829864
Munakata, N. and D.J. Klionsky. (2010). "Autophagy suite": Atg9 cycling in the cytoplasm to vacuole targeting pathway. Autophagy 6: 679-685. 20543572
Umemiya, R., T. Matsuo, T. Hatta, S. Sakakibara, D. Boldbaatar, and K. Fujisaki. (2007). Cloning and characterization of an autophagy-related gene, ATG12, from the three-host tick Haemaphysalis longicornis. Insect Biochem Mol Biol 37: 975-984. 17681237
Xie, Z. and D.J. Klionsky. (2007). Autophagosome formation: core machinery and adaptations. Nat. Cell Biol. 9: 1102-1109. 17909521