Control of ATG14 solubility and autophagy by MARCHF7/MARCH7-mediated ubiquitination

Emerging research has unequivocally demonstrated the significance of post-translational modifications (PTMs) of proteins in orchestrating macroautophagy/autophagy regulation. Ubiquitination is a common PTM of proteins that regulates their stability, activity, and localization, thus playing a crucial role in various cellular processes, including autophagy. In recent work, a ubiquitination-related study revealed that MARCHF7/MARCH7 promotes the mixed polyubiquitination of ATG14 at multiple sites, mainly through the linkages of K6, K11, and K63 ubiquitin chains. Consequently, mixed ubiquitination leads to substantial insoluble aggregation of ATG14/ATG14L/Barkor, reducing its interaction with STX17, and ultimately causing a decrease in autophagy flux. It is noteworthy that we have observed that this regulation may hold significant potential value for the autophagic degradation of protein aggregates, as the number of aggresome-like induced structures (ALISs) is markedly reduced in MARCHF7 knockout cells. This may have important potential implications for neurodegenerative diseases characterized by protein aggregation and impaired degradation.