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Core principles of autophagy initiation mechanisms

Nature Structural & Molecular Biology (2026)Cite this article

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Abstract

Autophagy is a conserved intracellular degradation system essential for maintaining cellular homeostasis and adapting to a variety of environmental or metabolic cues. Different types of autophagy are induced in response to various physiological signals through distinct mechanisms. In this Review, we highlight recent advances in understanding the molecular mechanisms that induce autophagic degradation of cytoplasmic material in bulk upon nutrient or energy deprivation, and those that trigger the selective autophagic removal of specific cellular components for their quality or quantity control. We discuss mechanistic principles shared across different types of autophagy, such as phase-separation-mediated assembly and activation of related factors, and the coordination between cargo recognition and membrane biogenesis, delineating how diverse mechanisms converge on core principles to ensure context-specific control of autophagy initiation.

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Fig. 1: Non-selective autophagy and selective autophagy.
Fig. 2: Assembly of autophagy initiation complexes.
Fig. 3: Initiation of selective autophagy.

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Acknowledgements

This work was supported in part by KAKENHI Grants-in-Aid for Scientific Research JP23K20044, JP24H00553 and JP25H01322 (to H.N.) and JP25K09544 (to T.K.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; AMED grant number JP21gm1410004 (to H.N.); and grants from the Takeda Science Foundation (to H.N.). We thank H. Zhang for critical reading of the manuscript and helpful comments. We also thank N. Matsuda for valuable discussions. We apologize to those whose relevant work could not be mentioned or included in the references because of space limitations.

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  1. Cell Biology Center, Institute of Integrated Research, Institute of Science Tokyo, Yokohama, Japan

    Tetsuya Kotani & Hitoshi Nakatogawa

  2. School of Life Science and Technology, Institute of Science Tokyo, Yokohama, Japan

    Hitoshi Nakatogawa

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Kotani, T., Nakatogawa, H. Core principles of autophagy initiation mechanisms. Nat Struct Mol Biol (2026). https://doi.org/10.1038/s41594-026-01752-4

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