Atg2a, an essential core member of the autophagy machinery, facilitates lipid flow between tethered membranes, which is crucial for autophagosome formation [1,2,3,5]. Autophagy is a highly conserved cellular process maintaining cellular homeostasis, and Atg2a's function in lipid transfer within this pathway is of great biological importance. Genetic models, such as knockout models, can be valuable in further elucidating its role.

Depletion of Atg2a-related proteins has significant impacts. For example, depletion of the endosome-localized protein ANKFY1, which binds to Atg2a, phenocopies Atg2a/b depletion, impairing autophagosome growth and autophagy flux [2]. In Neuro-2a cells, knocking down Atg2a, but not Atg2b, leads to impaired autophagy due to reduced autophagosome-lysosome fusion, while Atg2a overexpression can partially rescue fusion defects in Wdr45-and Wdr45b-deficient cells [4]. Also, in macrophages, the interaction between HCK and Atg2a inhibits autophagy flux, promoting renal inflammation and fibrosis [6]. Loss of WIPI4, which forms a complex with Atg2a, causes ferroptosis via an autophagy-independent mechanism by increasing Atg2a localization at endoplasmic reticulum-mitochondrial contact sites [7].

In summary, Atg2a is vital for autophagosome formation, autophagosome-lysosome fusion, and maintaining normal autophagy flux. Studies using gene-knockout models have revealed its significance in diseases like renal inflammation, fibrosis, and neurodegeneration related to ferroptosis. Understanding Atg2a's function through these models provides insights into disease mechanisms and potential therapeutic targets.

References:

1. van Vliet, Alexander R, Chiduza, George N, Maslen, Sarah L, Cherepanov, Peter, Tooze, Sharon A. 2022. ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation. In Molecular cell, 82, 4324-4339.e8. doi:10.1016/j.molcel.2022.10.017. https://pubmed.ncbi.nlm.nih.gov/36347259/

2. Wei, Bin, Fu, Yuhui, Li, Xiuzhi, Liu, Xiaoxia, Zhong, Qing. 2024. ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores. In Cell discovery, 10, 43. doi:10.1038/s41421-024-00659-y. https://pubmed.ncbi.nlm.nih.gov/38622126/

3. Otomo, Takanori, Maeda, Shintaro. 2019. ATG2A transfers lipids between membranes in vitro. In Autophagy, 15, 2031-2032. doi:10.1080/15548627.2019.1659622. https://pubmed.ncbi.nlm.nih.gov/31441376/

4. Zheng, Ze, Ji, Cuicui, Zhao, Hongyu, Zhao, Yan G. 2025. ATG2A acts as a tether to regulate autophagosome-lysosome fusion in neural cells. In Autophagy, , 1-12. doi:10.1080/15548627.2025.2479427. https://pubmed.ncbi.nlm.nih.gov/40083067/

5. Wang, Yang, Stjepanovic, Goran. 2025. ATG2A-WDR45/WIPI4-ATG9A complex-mediated lipid transfer and equilibration during autophagosome formation. In Autophagy, , 1-3. doi:10.1080/15548627.2025.2473388. https://pubmed.ncbi.nlm.nih.gov/40116844/

6. Chen, Man, Menon, Madhav C, Wang, Wenlin, He, John Cijiang, Wei, Chengguo. 2023. HCK induces macrophage activation to promote renal inflammation and fibrosis via suppression of autophagy. In Nature communications, 14, 4297. doi:10.1038/s41467-023-40086-3. https://pubmed.ncbi.nlm.nih.gov/37463911/

7. Zhu, Ye, Fujimaki, Motoki, Snape, Louisa, Fleming, Angeleen, Rubinsztein, David C. 2024. Loss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis. In Nature cell biology, 26, 542-551. doi:10.1038/s41556-024-01373-3. https://pubmed.ncbi.nlm.nih.gov/38454050/