{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWIPI2 is a key phosphatidylinositol 3‐phosphate (PI3P) effector that orchestrates the earliest steps of autophagosome biogenesis by coupling PI3P production with the recruitment of the ATG12–5–16L1 complex, which is essential for LC3 (ATG8) lipidation and autophagosomal membrane expansion. Mechanistically, WIPI2 is rapidly recruited to emerging autophagosomal structures—such as the omegasome—and, by binding directly to ATG16L1, it not only drives the localized assembly of the LC3 conjugation machinery but also allosterically activates the E3‐like function of the complex. Structural studies have revealed that specific regions of WIPI2 mediate this interaction, thereby bridging upstream PI3P signaling with the LC3 lipidation process."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its scaffolding role in autophagosome formation, the activity and expression of WIPI2 are tightly regulated by post‐translational modifications and interactions with signaling molecules. mTORC1, the central nutrient sensor, directly phosphorylates WIPI2 at serine 395, thereby promoting its interaction with the E3 ubiquitin ligase HUWE1 and triggering subsequent proteasomal degradation—a regulatory mechanism that modulates autophagic flux in response to metabolic cues. Moreover, phosphorylation events at other residues, such as S284 by ULK1, modulate the ability of WIPI2 to associate with membranes, whereas binding of STING to its PI3P‐binding motif can competitively inhibit canonical PI3P interactions, illustrating a complex network of regulation that integrates autophagy with innate immune responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWIPI2 function is also critical in selective autophagy pathways and cellular defense mechanisms, including antibacterial autophagy where its recruitment—facilitated by signaling kinases such as TBK1—ensures the encapsulation and clearance of intracellular pathogens. Furthermore, genetic and functional studies have implicated WIPI2 in human disease: mutations that impair its PI3P binding and interaction with the ATG12–5–16L1 complex result in diminished LC3 lipidation and autophagic flux, contributing to complex developmental disorders, while dysregulated WIPI2 expression is associated with defects in neutrophil differentiation and tumor cell proliferation, as observed in acute myeloid leukemia and hepatocellular carcinoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, the subcellular distribution of WIPI2 extends beyond autophagosomal membranes to include the endoplasmic reticulum, Golgi, and plasma membrane, underscoring its broader relevance in membrane dynamics. Its distinct localization patterns and interaction with other autophagic proteins not only make WIPI2 a central hub for the initiation and progression of autophagy but also a useful biomarker for assessing autophagic activity in physiological and disease contexts, as demonstrated by recent high‐throughput and clinical studies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": ""}]}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hannah E J Polson, Jane de Lartigue, Daniel J Rigden, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/auto.6.4.11863"}], "href": "https://doi.org/10.4161/auto.6.4.11863"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20505359"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20505359"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hannah C Dooley, Minoo Razi, Hannah E J Polson, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.70372"}], "href": "https://doi.org/10.7554/eLife.70372"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34505572"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34505572"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Wei Wan, Zhiyuan You, Li Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "mTORC1-Regulated and HUWE1-Mediated WIPI2 Degradation Controls Autophagy Flux."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2018.09.017"}], "href": "https://doi.org/10.1016/j.molcel.2018.09.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30340022"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30340022"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Wei Wan, Chuying Qian, Qian Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "STING directly recruits WIPI2 for autophagosome formation during STING-induced autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embj.2022112387"}], "href": "https://doi.org/10.15252/embj.2022112387"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36872914"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36872914"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Andrea Gubas, Eleanor Attridge, Harold Bj Jefferies, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WIPI2b recruitment to phagophores and ATG16L1 binding are regulated by ULK1 phosphorylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s44319-024-00215-5"}], "href": "https://doi.org/10.1038/s44319-024-00215-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39152217"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39152217"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "D Brigger, T Proikas-Cezanne, M P Tschan "}, {"type": "b", "children": [{"type": "t", "text": "WIPI-dependent autophagy during neutrophil differentiation of NB4 acute promyelocytic leukemia cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cddis.2014.261"}], "href": "https://doi.org/10.1038/cddis.2014.261"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24991767"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24991767"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Teresa Lm Thurston, Keith B Boyle, Mark Allen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Recruitment of TBK1 to cytosol-invading Salmonella induces WIPI2-dependent antibacterial autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embj.201694491"}], "href": "https://doi.org/10.15252/embj.201694491"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27370208"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27370208"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Musharraf Jelani, Hannah C Dooley, Andrea Gubas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A mutation in the major autophagy gene, WIPI2, associated with global developmental abnormalities."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awz075"}], "href": "https://doi.org/10.1093/brain/awz075"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30968111"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30968111"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Chunsheng Liu, Feng Li, Xiaoning Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WIPI2 depletion inhibits the growth of hepatocellular carcinoma cells through the AMPK signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2020.7531"}], "href": "https://doi.org/10.3892/or.2020.7531"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32323845"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32323845"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Tassula Proikas-Cezanne, Horst Robenek "}, {"type": "b", "children": [{"type": "t", "text": "Freeze-fracture replica immunolabelling reveals human WIPI-1 and WIPI-2 as membrane proteins of autophagosomes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1582-4934.2011.01339.x"}], "href": "https://doi.org/10.1111/j.1582-4934.2011.01339.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21564513"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21564513"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Simon G Pfisterer, Daniela Bakula, Alice Cezanne, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WIPI β-propellers at the crossroads of autophagosome and lipid droplet dynamics."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Soc Trans (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BST20140152"}], "href": "https://doi.org/10.1042/BST20140152"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25233424"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25233424"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Ann-Katrin Thost, Pierre Dönnes, Oliver Kohlbacher, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fluorescence-based imaging of autophagy progression by human WIPI protein detection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Methods (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymeth.2014.11.011"}], "href": "https://doi.org/10.1016/j.ymeth.2014.11.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25462558"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25462558"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Marwa Matboli, Ahmed E M Azazy, Seham Adel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evaluation of urinary autophagy transcripts expression in diabetic kidney disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Diabetes Complications (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jdiacomp.2017.06.009"}], "href": "https://doi.org/10.1016/j.jdiacomp.2017.06.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28760651"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28760651"}]}]}]}