{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ATG9A is a unique, evolutionarily conserved, multi‐spanning transmembrane protein that plays a critical role in autophagy by mediating membrane delivery and remodeling during autophagosome biogenesis. Studies in mammalian cells have shown that under basal conditions ATG9A resides in the trans‐Golgi network and endosomes but redistributes to peripheral, autophagosome‐positive compartments upon autophagy induction by starvation or pharmacological inhibition of MTORC1."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Its trafficking is tightly regulated by multiple factors: adaptor protein complexes such as AP‐4 and AP‐2 recognize sorting motifs in its cytosolic domains to mediate export from the Golgi"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": ", while p38 MAPK–dependent signaling and ULK1/AMPK‐mediated phosphorylation regulate its redistribution and association with autophagosomal membranes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structural studies have revealed that ATG9A forms a homotrimer with a central, solvent‐filled pore and laterally connected cavities, reminiscent of transporter proteins. These features enable ATG9A to function as a lipid scramblase that facilitates the redistribution (or “flipping”) of phospholipids between membrane leaflets—a function essential for membrane bending and the expansion of nascent autophagosomes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of selective autophagy such as mitophagy, ATG9A‐containing vesicles are recruited independently to damaged mitochondria, where proper assembly of these vesicles—regulated by factors including RAB7A—is necessary for the subsequent recruitment of downstream autophagy proteins and efficient mitochondrial sequestration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Moreover, a role for ATG9A has also been implicated in modulating innate immunity; for example, its colocalization with STING following dsDNA stimulation suggests that appropriate ATG9A function helps balance antiviral signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "16"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, genetic and biochemical studies have linked dysregulation of ATG9A trafficking to neurodegenerative diseases. For instance, mutations affecting components of the retromer or AP‐4 complexes cause ATG9A mislocalization, which in turn impairs autophagosome formation and promotes protein aggregate accumulation in neuronal cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}, {"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, ATG9A acts as an essential mediator of membrane delivery and lipid remodeling necessary for the initiation and expansion of autophagosomes. Its regulated trafficking and lipid scramblase activity integrate nutrient and stress signals with autophagic responses, thereby playing a central role in maintaining cellular homeostasis and innate immunity.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andrew R J Young, Edmond Y W Chan, Xiao Wen Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.03172"}], "href": "https://doi.org/10.1242/jcs.03172"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16940348"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16940348"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jemma L Webber, Sharon A Tooze "}, {"type": "b", "children": [{"type": "t", "text": "Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2009.321"}], "href": "https://doi.org/10.1038/emboj.2009.321"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19893488"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19893488"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Takahiro Yamada, Andrew R Carson, Isabella Caniggia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endothelial nitric-oxide synthase antisense (NOS3AS) gene encodes an autophagy-related protein (APG9-like2) highly expressed in trophoblast."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M413957200"}], "href": "https://doi.org/10.1074/jbc.M413957200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15755735"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15755735"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Rafael Mattera, Sang Yoon Park, Raffaella De Pace, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AP-4 mediates export of ATG9A from the "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "trans"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": "-Golgi network to promote autophagosome formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1717327114"}], "href": "https://doi.org/10.1073/pnas.1717327114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29180427"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29180427"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Kenta Imai, Feike Hao, Naonobu Fujita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Atg9A trafficking through the recycling endosomes is required for autophagosome formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.196196"}], "href": "https://doi.org/10.1242/jcs.196196"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27587839"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27587839"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Raffaella De Pace, Miguel Skirzewski, Markus Damme, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1007363"}], "href": "https://doi.org/10.1371/journal.pgen.1007363"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29698489"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29698489"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Ji-Man Park, Chang Hwa Jung, Minchul Seo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15548627.2016.1140293"}], "href": "https://doi.org/10.1080/15548627.2016.1140293"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27046250"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27046250"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Jemma L Webber, Sharon A Tooze "}, {"type": "b", "children": [{"type": "t", "text": "New insights into the function of Atg9."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2010.01.020"}], "href": "https://doi.org/10.1016/j.febslet.2010.01.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20083107"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20083107"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Vajira K Weerasekara, David J Panek, David G Broadbent, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Metabolic-stress-induced rearrangement of the 14-3-3ζ interactome promotes autophagy via a ULK1- and AMPK-regulated 14-3-3ζ interaction with phosphorylated Atg9."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00740-14"}], "href": "https://doi.org/10.1128/MCB.00740-14"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25266655"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25266655"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Shintaro Maeda, Hayashi Yamamoto, Lisa N Kinch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure, lipid scrambling activity and role in autophagosome formation of ATG9A."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Mol Biol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41594-020-00520-2"}], "href": "https://doi.org/10.1038/s41594-020-00520-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33106659"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33106659"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Carlos M Guardia, Xiao-Feng Tan, Tengfei Lian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2020.107837"}], "href": "https://doi.org/10.1016/j.celrep.2020.107837"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32610138"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32610138"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Eisuke Itakura, Chieko Kishi-Itakura, Ikuko Koyama-Honda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.094110"}], "href": "https://doi.org/10.1242/jcs.094110"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22275429"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22275429"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Koji Yamano, Chunxin Wang, Shireen A Sarraf, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endosomal Rab cycles regulate Parkin-mediated mitophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.31326"}], "href": "https://doi.org/10.7554/eLife.31326"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29360040"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29360040"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Tatsuya Saitoh, Naonobu Fujita, Takuya Hayashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0911267106"}], "href": "https://doi.org/10.1073/pnas.0911267106"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19926846"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19926846"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Catherine L Nezich, Chunxin Wang, Adam I Fogel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiT/TFE transcription factors are activated during mitophagy downstream of Parkin and Atg5."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.201501002"}], "href": "https://doi.org/10.1083/jcb.201501002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26240184"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26240184"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Yiping Huang, Rafael Guerrero-Preston, Edward A Ratovitski "}, {"type": "b", "children": [{"type": "t", "text": "Phospho-ΔNp63α-dependent regulation of autophagic signaling through transcription and micro-RNA modulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Cycle (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cc.11.6.19670"}], "href": "https://doi.org/10.4161/cc.11.6.19670"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22356768"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22356768"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Eszter Zavodszky, Matthew N J Seaman, Kevin Moreau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms4828"}], "href": "https://doi.org/10.1038/ncomms4828"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24819384"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24819384"}]}]}]}