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Review
. 2024 Nov;20(11):2373-2387.
doi: 10.1080/15548627.2024.2384349. Epub 2024 Aug 4.

Emerging roles of ATG9/ATG9A in autophagy: implications for cell and neurobiology

Jiyoung Choi  1   2 , Haeun Jang  1 , Zhao Xuan  3 , Daehun Park  1   2
Affiliations
Review

Emerging roles of ATG9/ATG9A in autophagy: implications for cell and neurobiology

Jiyoung Choi et al. Autophagy. 2024 Nov.

Abstract

Atg9, the only transmembrane protein among many autophagy-related proteins, was first identified in the year 2000 in yeast. Two homologs of Atg9, ATG9A and ATG9B, have been found in mammals. While ATG9B shows a tissue-specific expression pattern, such as in the placenta and pituitary gland, ATG9A is ubiquitously expressed. Additionally, ATG9A deficiency leads to severe defects not only at the molecular and cellular levels but also at the organismal level, suggesting key and fundamental roles for ATG9A. The subcellular localization of ATG9A on small vesicles and its functional relevance to autophagy have suggested a potential role for ATG9A in the lipid supply during autophagosome biogenesis. Nevertheless, the precise role of ATG9A in the autophagic process has remained a long-standing mystery, especially in neurons. Recent findings, however, including structural, proteomic, and biochemical analyses, have provided new insights into its function in the expansion of the phagophore membrane. In this review, we aim to understand various aspects of ATG9 (in invertebrates and plants)/ATG9A (in mammals), including its localization, trafficking, and other functions, in nonneuronal cells and neurons by comparing recent discoveries related to ATG9/ATG9A and proposing directions for future research.Abbreviation: AP-4: adaptor protein complex 4; ATG: autophagy related; cKO: conditional knockout; CLA-1: CLArinet (functional homolog of cytomatrix at the active zone proteins piccolo and fife); cryo-EM: cryogenic electron microscopy; ER: endoplasmic reticulum; KO: knockout; PAS: phagophore assembly site; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SV: synaptic vesicle; TGN: trans-Golgi network; ULK: unc-51 like autophagy activating kinase; WIPI2: WD repeat domain, phosphoinositide interacting 2.

Keywords: ATG proteins; ATG9; ATG9A; autophagy; lipid scramblase; phagophore expansion.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Cladogram and nomenclature of ATG9 proteins. The phylogenetic cladogram from a multiple sequence alignment of ATG9 proteins across different species. The amino acid sequences (NCBI) from each species were aligned using the alignment software MUSCLE [17], and the phylogenetic tree was created using the maximum likelihood method in MegaX [18] and then verified with panther tree viewer on ALLIANCE genome resources [19] and the ensembl gene tree [20]. The gene and protein nomenclature of each homolog are indicated on the right side. Notably, two homologs (A/B) are expressed in mammals and zebrafish, while only one homolog exists in flies, worms, yeast, and Arabidopsis.
Figure 2.
Figure 2.
The structure of the human ATG9A. (A) left panel: the topology of the human ATG9A monomer (full length; 1–839 amino acids). The numbers in red indicate the corresponding amino acid residues of each alpha helix. Dark red regions show the two membrane-embedded helices that do not penetrate the membrane. Right panel: the 3D reconstruction from the AlphaFold prediction [43] of human ATG9A (AF-Q7Z3C6-F1-model_v1). The structure is color-coded by the disordered score. (B) the structure of the human ATG9A trimer generated from the cryo-EM density map (EMDB: EMD-21876, PDB: 6WR4). Each monomer is colored differently, and gray disks outline the edges of the membrane. Note that this model does not represent the full-length protein, and shows residues 36 to 587, with missing loop residues 96–108 and 536–538, and includes two additional helices in the C-terminal domain among a total of 839 amino acids in a monomer. The arrows show the locations of the three different types of pores. The structural images were generated and modified using the RCSB PDB webserver (https://www.rcsb.org) [44] and 3D viewers Mol* viewer [45], respectively.
Figure 3.
Figure 3.
ATG9/ATG9A trafficking in nonneuronal cells and working models for phagophore growth. Upper panel: trafficking of ATG9/ATG9A in nonneuronal cells and its involvement in the autophagic process. Proteins shown in purple are potential ATG9/ATG9A interactors according to previous proteomic studies. Lower panel: proposed models for ATG9/ATG9A-mediated phagophore growth and the remaining questions.
Figure 4.
Figure 4.
Trafficking and function of ATG9/ATG9A in neurons. ATG9/ATG9A is believed to be transported to nerve terminals, undergo activity-dependent exo- and endocytosis, and localize to distinct vesicle pools at presynapses. However, the details of its precise roles in nerve terminals remain unclear. Potential ATG9A interactors based on proteomic analyses are shown in purple. The asterisk (*) indicates evidence from worms (C. elegans).
Figure 5.
Figure 5.
ATG9/ATG9A-deficient phenotypes. Loss of ATG9/ATG9A leads to various defects at different levels.
See this image and copyright information in PMC

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