Did evolution choose Atg11 as the scaffolding platform beyond selective autophagy?

ABSTRACT

It has been well established that Atg11 plays a critical role in selective macroautophagy/autophagy, but not in nonselective autophagy in the budding yeast Saccharomyces cerevisiae. However, its mammalian ortholog RB1CC1/FIP200 is indispensable for both types of autophagy, and the molecular mechanism behind its function is a mystery. Recently, Pan et al. showed that in the fission yeast Schizosaccharomyces pombe, Atg11 could also promote nonselective autophagy via activation of Atg1 kinase. These results prompt an interesting idea that Atg11 might have gained an additional ability to mediate nonselective autophagy through evolution.

Autophagy is an evolutionarily conserved catabolic process in which cytosolic cargos or damaged organelles can be engulfed by a specialized transient compartment, the phagophore, which matures into a double-membrane structure called an autophagosome. The initiation of autophagosome biogenesis requires the recruitment and activation of Atg1 kinase at the phagophore assembly site (PAS). In the budding yeast S. cerevisiae, it is well established that two scaffold proteins, Atg11 and Atg17, contribute to Atg1 activation during selective autophagy and nonselective autophagy (also called “bulk autophagy”), respectively [1–3]. Interestingly, both S. cerevisiae Atg11 and human RB1CC1 contain an Atg17-like domain; this raises the tantalizing hypothesis that Atg11 might be an intermediate between Atg17 and RB1CC1, and that during evolution the function of Atg17 might be replaced by Atg11 and, ultimately, RB1CC1.

A recent discovery from the fission yeast S. pombe suggested that this might indeed be the case. Pan et al. found that S. pombe Atg11, like its mammalian ortholog, is required for bulk autophagy [4]. Using an ATP-γ-S based nonradioactive kinase assay, they showed that under nitrogen-starvation conditions, the phosphorylation of Atg1 remains intact in atg13∆ and atg17∆ strains, but is severely impaired in an atg11∆ strain, implying that Atg11 is indispensable for the activation of Atg1 kinase. Further truncation analysis narrowed down the region responsible for Atg11’s function in Atg1 activation into a 62 amino-acid region (522–583). Pan et al. found that this region contains two functional domains: Atg11 522–544 mediates the direct interaction with the C-terminal microtubule interacting and transport (MIT) domains of Atg1, whereas Atg11 546–583 promotes self-homodimerization. To gain mechanistic insight into how Atg11 activates Atg1 kinase, Pan et al. fused Atg1 with a leucine zipper domain and found this artificially dimerized Atg1 can be activated in the absence of Atg11, supporting the idea that Atg11 activates Atg1 kinase by bringing two Atg1 molecules together. This characterization of the kinase-dead atg1 mutant indicated that such Atg1 dimerization is followed by cis-phosphorylation.

From the perspective of evolution, this study suggested that to better understand the mechanism of Atg1 complex activation, fission yeast might be selected as an ideal system, considering the evolutionary gap between budding yeast and mammals. Many interesting questions could be addressed based on the comparisons among RB1CC1 in mammals and Atg11 in two yeasts: During evolution, what changes provided Atg11 with the ability to activate bulk autophagy? How is the interaction between Atg11 and Atg1 regulated by autophagy-inducing signals such as TOR inactivation? If S. pombe Atg11 can support both nonselective and selective autophagy, how are these two processes temporally and spatially regulated? Previous studies suggest that S. pombe Atg17 is also required for nonselective autophagy; thus, what are the different functions of Atg11 and Atg17 in nonselective autophagy in S. pombe [5]? Elucidation of the detailed mechanisms of Atg1 complex activation and function across different species should provide a more complete picture of autophagy regulation.

Funding Statement

This work was supported by the National Institute of General Medical Sciences [GM131919].

Disclosure statement

No potential conflict of interest was reported by the authors.