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Li-Lin Du’s laboratory reveals molecular mechanisms governing Atg1 kinase activation in fission yeast

Publication Date:2020/09/16
On September 10, 2020, Li-Lin Du’s laboratory published online a paper titled “Atg1 kinase in fission yeast is activated by Atg11-mediated dimerization and cis-autophosphorylation” in eLife. This paper reports that in the fission yeast Schizosaccharomyces pombe, the activity of the autophagy kinase Atg1 requires Atg11-mediated dimerization and Atg1 activation occurs through cis-autophosphorylation.

Autophagy is a fundamental biological process. Autophagy is executed by a set of autophagy-related (Atg) proteins conserved from yeasts to mammals. Atg1 (called ULK1 in mammals) is a serine/threonine kinase whose activity is essential for autophagy. Studies using the budding yeast Saccharomyces cerevisiae have provided insights into how Atg1 is activated, but it is unclear whether other eukaryotes use similar mechanisms to control Atg1 activity.

In this study, the authors found that, in fission yeast, Atg1 kinase activity is controlled in a way surprisingly different from in budding yeast. They showed that Atg11, which is dispensable for bulk autophagy in S. cerevisiae, is essential for bulk autophagy and Atg1 activity in S. pombe. On the other hand, Atg13 and Atg17, which are required for Atg1 activation during bulk autophagy in S. cerevisiae, are dispensable for Atg1 activity in S. pombe. Because the ortholog of Atg11 in mammals is also required for bulk autophagy, it is likely that the activation mechanism of Atg1 is more similar between S. pombe and mammals.

The authors dissected the molecular details of how Atg11 activates Atg1 and showed that Atg11 acts by dimerizing Atg1. Furthermore, they demonstrated that dimerization-mediated Atg1 activation occurs through cis-autophosphorylation, thereby overturning the widely assumed but never tested notion that Atg1 is activated by trans-autophosphorylation.

In sum, this study discovers that Atg11 is required for Atg1 kinase activity in fission yeast, reveals that Atg11 promotes Atg1 activation by dimerizing Atg1, and demonstrates that Atg1 activation can occur through cis-autophosphorylation. These findings significantly advance the understanding of the molecular mechanisms governing Atg1 activation and the functions of the Atg11 family proteins.

Zhao-Qian Pan is the first author of this paper. Dr. Li-Lin Du is the corresponding author. Other contributors include Guang-Can Shao, Xiao-Man Liu, Quan Chen, and Meng-Qiu Dong. This work was supported by the Chinese Ministry of Science and Technology and the Beijing municipal government.

Link to the paper: https://elifesciences.org/articles/58073