MARCH7-mediated ubiquitination decreases the solubility of ATG14 to inhibit autophagy

Autophagy is a fundamental biological process critical to all eukaryotic cellular life. Although autophagy has been increasingly studied, how its process is precisely coordinated remains an open question. ATG14 (ATG14L/Barkor) is known to play a crucial role in both autophagosome formation and autophagosome-lyso-some fusion. However, how ATG14 is regulated, especially at the post-translation level, is still not clear. Here, we report that MARCH7 (membrane-associated ring-CH-type finger 7), an E3 ubiquitin ligase, inhibits auto-phagy by ubiquitinating ATG14. MARCH7 significantly promotes K6-, K11-, and K63-linked mixed poly-ubiquitination on ATG14, triggering the aggregation of ATG14 and reducing its solubility in cells. Functionally, we find that MARCH7 depletion decreases the number of aggresome-like induced structures (ALISs). Mech-anistically, we show that ubiquitinated ATG14 has fewer interactions with STX17, leading to the inhibition of autophagy flux. Collectively, our study reveals a mechanism in regulating autophagy and suggests a potential strategy for the treatment of autophagy-related diseases.

Automated summary

This study reveals a mechanism of regulating autophagy by demonstrating that MARCH7 inhibits autophagy through ubiquitinating ATG14, leading to reduced interactions between ATG14 and STX17 and decreased autophagy flux.