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

February 10, 2023

Autophagy, or “self-eating”, is an essential cellular quality control mechanism that clears the cell of protein aggregates and damaged organelles. This mechanism is inactive under normal conditions and only triggered upon persistent cellular stress. Researchers from the labs of Yasin Dagdas at the Gregor Mendel Institute of Molecular Plant Biology (GMI) of the Austrian Academy of Sciences and Elif Karagöz at the Max Perutz Labs uncover a molecular switch that regulates autophagy in plants. Combining evolutionary analysis with a mechanistic experimental approach, they demonstrate that this regulatory mechanism is conserved in eukaryotes. The findings were published on February 10th in the EMBO Journal.

Persistent cellular stress, resulting from disturbances of cellular homeostasis, impairs cell fitness and lifespan. Cellular stress may develop, for example, when ribosomes collide while translating faulty mRNAs. As a result, cells get overburdened with unfinished and improperly formed protein products that form toxic protein aggregates. During cellular stress, cells can call on an arsenal of quality control (QC) mechanisms to restore homeostasis. Cells experiencing prolonged stress in the endoplasmic reticulum (ER), the cellular center for protein synthesis and transport, initiate an ER-specific autophagic pathway called “ER-phagy” to selectively remove damaged ER. When ribosomes collide on the ER, another QC pathway, called “UFMylation”, cooperates with ER-phagy to get rid of incompletely synthesized proteins at the ER membrane. UFMylation is an enigmatic QC pathway based on a protein post-translational modification that resembles ubiquitin and its functions are still being deciphered.

Now, a team of researchers at the Vienna BioCenter, including multiple members of our Special Research Program, uncover an ancient molecular switch that regulates ER-phagy. Using a combination of evolutionary biology and mechanistic experimentation, the researchers demonstrate that the competition between two ubiquitin-like molecules, UFM1 and ATG8 creates a molecular switch in the master regulator C53, thus initiating ER-phagy.

Read the full story in the GMI news here.

Publication:

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^*:

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

EMBO Journal. 2023 February 10.

DOI: 10.15252/embj.2022112053

^#These authors contributed equally to this work.

*Co-corresponing authors.

Graphical Synopsis. Phylogenomic profiling has shown that UFMylation coevolves with the shuffled ATG8-interacting motifs (sAIMs) in the ER-phagy receptor C53. Further mechanistic analyses demonstrated that sAIMs regulate C53-mediated autophagy by competitively binding UFM1 and ATG8. ©Picchianti et al., EMBO J. (2023) https://doi.org/10.15252/embj.2022112053