Shuffled ATG8 interacting motifs form an ancestral bridge between UFMylation and autophagy

Lorenzo Picchianti, Víctor Sánchez de Medina Hernández, Ni Zhan, Nicholas AT Irwin, Roan Groh, Madlen Stephani, Harald Hornegger, Rebecca Beveridge, Justyna Sawa‐Makarska, Thomas Lendl, Nenad Grujic, Christin Naumann, Sascha Martens, Thomas A Richards, Tim Clausen, Silvia Ramundo, G Elif Karagöz, Yasin Dagdas

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Abstract

UFMylation involves the covalent modification of substrate proteins with UFM1 (Ubiquitin‐fold modifier 1) and is important for maintaining ER homeostasis. Stalled translation triggers the UFMylation of ER‐bound ribosomes and activates C53‐mediated autophagy to clear toxic polypeptides. C53 contains noncanonical shuffled ATG8‐interacting motifs (sAIMs) that are essential for ATG8 interaction and autophagy initiation. However, the mechanistic basis of sAIM‐mediated ATG8 interaction remains unknown. Here, we show that C53 and sAIMs are conserved across eukaryotes but secondarily lost in fungi and various algal lineages. Biochemical assays showed that the unicellular alga Chlamydomonas reinhardtii has a functional UFMylation pathway, refuting the assumption that UFMylation is linked to multicellularity. Comparative structural analyses revealed that both UFM1 and ATG8 bind sAIMs in C53, but in a distinct way. Conversion of sAIMs into canonical AIMs impaired binding of C53 to UFM1, while strengthening ATG8 binding. Increased ATG8 binding led to the autoactivation of the C53 pathway and sensitization of Arabidopsis thaliana to ER stress. Altogether, our findings reveal an ancestral role of sAIMs in UFMylation‐dependent fine‐tuning of C53‐mediated autophagy activation.
Original languageEnglish
Article numbere112053
Number of pages25
JournalThe EMBO journal
Volume42
Issue number10
Early online date10 Feb 2023
DOIs
Publication statusPublished - 15 May 2023

Keywords

  • ER-phagy
  • phylogenomics
  • ribosome stalling
  • selective autophagy

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