Scientists Discover Molecular “Switch” for Autophagy

Autophagy, a cellular quality control mechanism that clears cells of damaged organelles and protein aggregates, has been the subject of recent research by scientists at the Gregor Mendel Institute of Molecular Plant Biology and the Max Perutz Labs. The team has uncovered a molecular switch that regulates autophagy in plants and eukaryotes.

Cellular stress can cause cells to become overburdened with unfinished and improperly formed protein products that form toxic protein aggregates. In response, cells initiate an autophagic pathway called “ER-phagy” to selectively remove damaged endoplasmic reticulum (ER) and restore homeostasis. By combining evolutionary biology and mechanistic experimentation, the Vienna team have demonstrated that the competition between two ubiquitin-like molecules, UFM1 and ATG8, creates a molecular switch in the master regulator C53, initiating ER-phagy.

The researchers found that C53, a protein that interacts with both ATG8 and UFM1, contains an intrinsically disordered region with three “shuffled AIMs” (sAIMs) and one canonical AIM (cAIM). UFM1 preferentially binds to sAIM1 and sAIM2, while ATG8 has a higher preference for the cAIM motif.

By introducing mutations that strengthened ATG8’s binding to C53 and impaired UFM1’s binding, the researchers showed that sAIMs are essential for regulating C53-mediated ER-phagy and ER stress tolerance.

Further analysis by the team demonstrated that C53-mediated autophagy is conserved among eukaryotes and that C53 co-evolved with the UFMylation pathway. In species that have lost UFM1, their C53 also lost its sAIMs, indicating a highly conserved functional link between C53 and UFMylation.

The researchers went on to demonstrate that the unicellular algae Chlamydomonas reinhardtii has a functional UFMylation pathway and that the molecular switch described in plants also operates in this species.

These findings offer a new level of insight into the molecular mechanisms of autophagy and could lead to new strategies for managing cellular stress, as well as improving cell fitness and lifespan. The research, published in the EMBO Journal, highlights the importance of studying autophagy in different organisms and provides a foundation for future studies in this field.