Laboratory of Molecular Membrane Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, 371-8512, Japan.
Laboratory of Molecular Traffic, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, 371-8512, Japan.
Nat Commun. 2024 Feb 17;15(1):1460. doi: 10.1038/s41467-024-45863-2.
Allophagy is responsible for the selective removal of paternally inherited organelles, including mitochondria, in Caenorhabditis elegans embryos, thereby facilitating the maternal inheritance of mitochondrial DNA. We previously identified two key factors in allophagy: an autophagy adaptor allophagy-1 (ALLO-1) and TBK1/IKKε family kinase IKKE-1. However, the precise mechanisms by which ALLO-1 and IKKE-1 regulate local autophagosome formation remain unclear. In this study, we identify two ALLO-1 isoforms with different substrate preferences during allophagy. Live imaging reveals a stepwise mechanism of ALLO-1 localization with rapid cargo recognition, followed by ALLO-1 accumulation around the cargo. In the ikke-1 mutant, the accumulation of ALLO-1, and not the recognition of cargo, is impaired, resulting in the failure of isolation membrane formation. Our results also suggest a feedback mechanism for ALLO-1 accumulation via EPG-7/ATG-11, a worm homolog of FIP200, which is a candidate for IKKE-1-dependent phosphorylation. This feedback mechanism may underlie the ALLO-1-dependent initiation and progression of autophagosome formation around paternal organelles.
自噬负责选择性去除包括线粒体在内的父源性细胞器，从而促进线粒体 DNA 的母系遗传。我们之前鉴定了自噬过程中的两个关键因子：自噬衔接蛋白 ALLO-1 和 TBK1/IKKε 家族激酶 IKKE-1。然而，ALLO-1 和 IKKE-1 调节局部自噬体形成的确切机制仍不清楚。在这项研究中，我们鉴定了两种具有不同底物偏好的 ALLO-1 同工型。活细胞成像揭示了 ALLO-1 定位的逐步机制，包括快速识别货物，随后 ALLO-1 聚集在货物周围。在 ikke-1 突变体中，货物的识别不受影响，而是 ALLO-1 的积累受到损害，导致隔离膜形成失败。我们的结果还表明，通过 EPG-7/ATG-11（一种线虫同源物 FIP200 的候选物），可能存在一种反馈机制来促进 ALLO-1 的积累，EPG-7/ATG-11 是 IKKE-1 依赖性磷酸化的候选物。这种反馈机制可能是 ALLO-1 依赖性父源性细胞器周围自噬体形成起始和进展的基础。
