New mechanism in regulating selective autophagy

2022-05-10 Global Communications

Autophagy is crucial for maintaining cellular homeostasis. It can be divided into non-selective autophagy and selective autophagy, both of which exert significant functions. Mitophagy, ribosomal autophagy, endoplasmic reticulum autophagy, and peroxisomal autophagy all belong to selective autophagy. Selective autophagy is closely associated with major human diseases, such as neurodegenerative diseases and metabolic diseases. Clarifying molecular mechanisms of selective autophagy can provide a theoretical basis for the development of related drugs or other treatments. 

In selective autophagy, cargo receptors recognize specific targets with degradation signals and interact with LC3 (Atg8 in yeast and plant cells). Atg11 with four coil-coiled domains (i.e. CC1, CC2, CC3 and CC4) exhibits as a scaffold protein in almost all types of selective autophagy, which is considered a marker protein for selective autophagy. It binds to substrate receptors through the CC4 domain, when interacting with the autophagy core protein Atg1 through the CC2 and CC3 domains, thereby recruiting substrates to autophagosomes. Though part of Atg11’s roles in selective autophagy have been revealed, how Atg11 activity is regulated remains to be explored by further investigation.

On April 15, the research group led by Prof. YI Cong from the Zhejiang University School of Basic Medicine/the First Affiliated Hospital of the Zhejiang University School of Medicine, published an article entitled Atg1-mediated Atg11 phosphorylation is required for selective autophagy by regulating autophagy in the journal Autophagy, uncovering a new mechanism by which Atg11 regulates selective autophagy.

In this study, the researchers found that Atg11 was phosphorylated when yeast cells were subjected to rapamycin treatment, nitrogen starvation, or glucose starvation. Next, the group discovered that Atg11 is a direct substrate of the kinase Atg1. In vitro phosphorylation experiments revealed that the Atg11 CC4 domain, which is responsible for binding to the receptor protein, was phosphorylated by Atg1. The results strongly suggested that the process of Atg11 binding to selective autophagy receptors is regulated by Atg1 kinase activity. In order to identify its phosphorylation sites, the Atg11 CC4 obtained from in vitro phosphorylation experiments was analyzed by mass spectrometry, and S949, S1057, and S1064 were identified as the phosphorylation sites of Atg1-mediated phosphorylation of Atg11. Further functional analysis experiments showed that mutations at these three sites curb selective autophagy due to the incapability of Atg11 binding to selective autophagy receptors (Figure 1).


Figure 1. Model for the regulation of selective autophagy by Atg1-mediated Atg11 phosphorylation 

In conclusion, Atg11 regulates the progression of selective autophagy via switching its phosphorylation status then affecting its binding ability to selective autophagy receptors. This discovery expands our understanding of the regulatory mechanism underlying the binding between Atg11 and selective receptors. As one of the reviewers said, I find this study reveals a new layer of regulation in selective autophagy.


Source: School of Medicine, Zhejiang University