Adriaenssens Elias, Schaar Stefan, Cook Annan S I, Stuke Jan F M, Sawa-Makarska Justyna, Nguyen Thanh Ngoc, Ren Xuefeng, Schuschnig Martina, Romanov Julia, Khuu Grace, Uoselis Louise, Lazarou Michael, Hummer Gerhard, Hurley James H, Martens Sascha
Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria.
Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna, Austria.
Nat Cell Biol. 2025 Jul 25. doi: 10.1038/s41556-025-01712-y.
Selective autophagy is a lysosomal degradation pathway that is critical for maintaining cellular homeostasis by disposing of harmful cellular material. Although the mechanisms by which soluble cargo receptors recruit the autophagy machinery are becoming increasingly clear, the principles governing how organelle-localized transmembrane cargo receptors initiate selective autophagy remain poorly understood. Here we demonstrate that the human transmembrane cargo receptors can initiate autophagosome biogenesis not only by recruiting the upstream FIP200/ULK1 complex but also via a WIPI-ATG13 complex. This latter pathway is employed by the BNIP3/NIX receptors to trigger mitophagy. Additionally, other transmembrane mitophagy receptors, including FUNDC1 and BCL2L13, exclusively use the FIP200/ULK1 complex, whereas FKBP8 and the ER-phagy receptor TEX264 are capable of utilizing both pathways to initiate autophagy. Our study defines the molecular rules for initiation by transmembrane cargo receptors, revealing remarkable flexibility in the assembly and activation of the autophagy machinery, with important implications for therapeutic interventions.
选择性自噬是一种溶酶体降解途径，通过清除有害的细胞物质对维持细胞内稳态至关重要。尽管可溶性货物受体招募自噬机制的过程越来越清晰，但细胞器定位的跨膜货物受体启动选择性自噬的原理仍知之甚少。在这里，我们证明人类跨膜货物受体不仅可以通过招募上游FIP200/ULK1复合物，还可以通过WIPI-ATG13复合物启动自噬体生物合成。BNIP3/NIX受体采用后一种途径触发线粒体自噬。此外，其他跨膜线粒体自噬受体，包括FUNDC1和BCL2L13，仅使用FIP200/ULK1复合物，而FKBP8和内质网自噬受体TEX264能够利用这两种途径启动自噬。我们的研究定义了跨膜货物受体启动自噬的分子规则，揭示了自噬机制组装和激活过程中的显著灵活性，对治疗干预具有重要意义。
