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EMBO Rep. 2017 May;18(5):765-780. doi: 10.15252/embr.201643146. Epub 2017 Mar 22.

Conserved Atg8 recognition sites mediate Atg4 association with autophagosomal membranes and Atg8 deconjugation.

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Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands.
Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.
Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories (MFPL), Vienna Biocenter (VBC), University of Vienna, Vienna, Austria.
Department of Biology, Institute of Biochemistry, Swiss Federal Institute of Technology, Zurich, Switzerland.
Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands


Deconjugation of the Atg8/LC3 protein family members from phosphatidylethanolamine (PE) by Atg4 proteases is essential for autophagy progression, but how this event is regulated remains to be understood. Here, we show that yeast Atg4 is recruited onto autophagosomal membranes by direct binding to Atg8 via two evolutionarily conserved Atg8 recognition sites, a classical LC3-interacting region (LIR) at the C-terminus of the protein and a novel motif at the N-terminus. Although both sites are important for Atg4-Atg8 interaction in vivo, only the new N-terminal motif, close to the catalytic center, plays a key role in Atg4 recruitment to autophagosomal membranes and specific Atg8 deconjugation. We thus propose a model where Atg4 activity on autophagosomal membranes depends on the cooperative action of at least two sites within Atg4, in which one functions as a constitutive Atg8 binding module, while the other has a preference toward PE-bound Atg8.


LC3; autophagosome; autophagy; deconjugation; phagophore assembly site

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