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REVIEW article

Front. Cell Dev. Biol.
Sec. Membrane Traffic and Organelle Dynamics
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1532050
This article is part of the Research Topic Autophagy Beyond Degradation: Unraveling the Secretory Function of the Endo-lysosomal System View all 4 articles

Mechanisms and Roles of Membrane-Anchored ATG8s

Provisionally accepted
Soo-Kyeong Lee Soo-Kyeong Lee 1Sang-Won Park Sang-Won Park 2Deok-Jin Jang Deok-Jin Jang 2Jin-A Lee Jin-A Lee 1*
  • 1 Hannam University, Daejeon, Republic of Korea
  • 2 Kyungpook National University, Daegu, North Gyeongsang, Republic of Korea

The final, formatted version of the article will be published soon.

    Autophagy-related protein 8 (ATG8) family proteins, including LC3 and GABARAP subfamilies, are pivotal in canonical autophagy, driving autophagosome formation, cargo selection, and lysosomal fusion. However, recent studies have identified non-canonical roles for lipidated ATG8 in processes such as LC3-associated phagocytosis (LAP), LC3-associated endocytosis (LANDO), and lipidated ATG8-mediated secretory autophagy. These pathways expand ATG8's functional repertoire in immune regulation, membrane repair, and pathogen clearance, as ATG8 becomes conjugated to single-membrane structures (e.g., phagosomes and lysosomes). This review examines the molecular mechanisms of ATG8 lipidation, focusing on its selective conjugation to phosphatidylethanolamine (PE) in autophagy and phosphatidylserine (PS) in CASM. We highlight LIR-based probes and LC3/GABARAPspecific deconjugases as critical tools that allow precise tracking and manipulation of ATG8 in autophagic and non-autophagic contexts. These advancements hold therapeutic promise for treating autophagy-related diseases, including cancer and neurodegenerative disorders, by targeting ATG8-driven pathways that maintain cellular homeostasis.

    Keywords: Autophagy, LC3/GABARAP, LIR motif, Non-canonical autophagy, Lando, LAP, probe, Deconjugase

    Received: 21 Nov 2024; Accepted: 09 Jan 2025.

    Copyright: © 2025 Lee, Park, Jang and Lee. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jin-A Lee, Hannam University, Daejeon, Republic of Korea

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.