Abstract
Autophagy is a catabolic degradation process and maintains cellular homeostasis. And autophagy is activated in response to various stress conditions. Although O-GlcNAcylation functions a sensor for nutrient and stress, the relationship between O-GlcNAcylation and autophagy is largely unknown. Here, we identified that ATG4B is novel target for O-GlcNAcylation under metabolic stress condition. Treatment with PugNAc, an O-GlcNAcase inhibitor increased activation of autophagy in SH-SY5Y cells. Both bimolecular fluorescence complementation and immunoprecipitation assay indicated that OGT directly interacts with ATG4B in SH-SY5Y cells. We also found that the O-GlcNAcylated ATG4B was increased in autophagy activation conditions, and down-regulation of OGT reduces O-GlcNAcylation of ATG4B under low glucose condition. Furthermore, the proteolytic activity of ATG4B for LC3 cleavage was enhanced in PugNAc-treated cells. Taken together, these results imply that O-GlcNAcylation of ATG4B regulates autophagy activation by increasing its proteolytic activity under metabolic stress condition.
Highlights
Autophagy functions under various stress conditions [1, 2]
We identified ATG4B as a novel substrate for O-GlcNAcylation
To explore the effect of O-GlcNAcylation on autophagy, we examined the effect of PugNAc treatment on autophagy level
Summary
Autophagy functions under various stress conditions [1, 2]. Autophagy is regulated by multiple signaling pathways and autophagy-related proteins (ATGs) essentially control the process [1, 2]. Autophagy is initiated with the formation of the phagophore, which is mediated by ULK1 and class 3-kinase complex [9]. Elongation and maturation of autophagosomes are performed by two ubiquitin-like reactions [10]. ATG7, ATG10, and the ATG5-ATG12-ATG6 complex elongate the pro-autophagosomal membrane [10]. LC3 is produced as a precursor protein and generated LC3-I by the protease ATG4B, it is conjugated with phosphatidylethanolamine (PE) in an ubiquitin-like reaction to generate LC3-II. LC3-II is targeted to the elongating autophagosome membrane [12, 13]. The LC3-II on the cytoplasmic location of autolysosome is recycled after delipidation of PE, which is performed by ATG4B [14]
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