Deacetylation Of Nuclear LC3by Sirt1Is Essential To Autophagy

Autophagy is a basic catabolic mechanism by which cellular compartments are enveloped into a double-membraned vesicle and shuttled to lysosomes for degradation. Microtubule-associated protein1light chain3(LC3) is a key autophagy-related protein which is recruited to autophagic membrane for autophagosome formation and autophagosome-lysosome fusion. In addition to location in the cytosol, LC3is also abundant in the nucleus, but the function and essentiality of LC3in the nucleus remains enigmatic. Here, we provided evidence that LC3deacetylation in the nucleus is crucial for autophagosome formation. We showed LC3translocated from the nucleus to the cytosol upon autophagic stimuli, and was the main source of membrane-associated LC3. During autophagy, LC3was deacetylated in the nucleus by deacetylase Sirtl. Then the deacetylated LC3interacted with Diabetes and Obesity Regulated gene (DOR) and export from the nucleus. We further identified that K49and K51of LC3were the main acetylation sites, and deacetylation at these sites was requried for LC3to interact with E1-like enzyme Atg7and subsequent PE conjugation. Altogether, these data suggest that deacetylation of LC3in the nucleus by Sirtl is a critical step essential to LC3lipidation and autophagosome formation.