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An expanding repertoire of E3 ligases in membrane Atg8ylation

Nature Cell Biology volume 26, pages 307–308 (2024)Cite this article

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In mammalian cells, membrane Atg8ylation has been historically referred to as ‘MAP1LC3 lipidation’, until recently being nearly synonymous with autophagy2. The ATG12–ATG5 conjugate was thought to combine exclusively with ATG16L1 to form the sole known E3 ligase within the canonical autophagy pathway2. During autophagy, WIPI2, an effector of a stress-signalling phospholipid, phosphatidylinositol-3-phosphate (PtdIns3P or PI3P), binds to ATG16L18 and docks the ATG12–ATG5–ATG16L1 E3 ligase to PI3P-marked membranes (Fig. 1b,i). It has, however, become increasingly evident that LC3 lipidation occurs on endomembranes other than autophagosomes11 (Fig. 1c) and that ATG16L1 can be guided to membranes by V-ATPase12 (Fig. 1b,ii) instead of WIPI2. In recent findings, sphingomyelin, present on the cytofacial side of perturbed endolysosomal membranes, recruits TECPR1 to form an ATG12–ATG5–TECPR1 E3 ligase that guides Atg8ylation5,6,7 (Fig. 1b,iii). We draw attention to an unmet need to match the expanding repertoire of non-autophagic membranes undergoing Atg8ylation (Fig. 1c) with a currently limited spectrum of E3 ligases. The examples include conventional phagosomes, endolysosomal compartments, exocytic organelles, endoplasmic reticulum (ER) and lipid droplets (Fig. 1c). Of note, the delimiting membrane of lipid droplets is a hemilayer of phospholipids and thus the targets that undergo Atg8ylation are not limited to double or single membranes, with the minimal substrate being a phospholipid monolayer.

How many alternative Atg8ylation E3 ligases exist? Given that the ubiquitination system includes 600 E3 ligases, then it is likely that there are at least a few more. On response to luminal changes in pH, ATG16L1 binds to the V1 subunit of V-ATPase and recruits ATG16L1 complexed with ATG12–ATG5 to membranes of the endolysosomal system directing Atg8ylation12,13,14. We speculate that there are additional adaptors of this type, with hints that can be found in the literature such as NOD2–IRGM–ATG16L1 complexes15. Is ATG16L1 a mandatory component of Atg8ylation E3 ligases? Recent studies5,6,7 have shown ATG16L1 substitution by TECPR1 in complexes with ATG12–ATG5 (Fig. 1c,iii). We postulate that several Atg8ylation E3 ligases exist, potentially mirroring the wealth of E3 ligases in the ubiquitination system, which should spur interest and further studies in this direction.

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Fig. 1: Membrane Atg8ylation and its E3 ligases.

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Acknowledgements

This work was supported by National Institutes of Health (NIH) grants R37AI042999, R01AI111935 and P20GM121176 to V.D., and NIH grant GM131919 to D.J.K.

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  1. Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence and Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, USA

    Vojo Deretic

  2. Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA

    Daniel J. Klionsky

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Correspondence to Vojo Deretic.

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Deretic, V., Klionsky, D.J. An expanding repertoire of E3 ligases in membrane Atg8ylation. Nat Cell Biol 26, 307–308 (2024). https://doi.org/10.1038/s41556-023-01329-z

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