Deacetylation of nuclear LC3 drives autophagy initiation under starvation

Rui Huang, Yinfeng Xu, Wei Wan, Xin Shou, Jiali Qian, Zhiyuan You, Bo Liu, Chunmei Chang, Tianhua Zhou,Jennifer Lippincott-Schwartz, and Wei Liu

 Mol Cell. 2015 Feb 5;57(3):456-66.

Speaker: Yin-Ping Wang (王尹平)                               Time: 13:10~14:00, Oct. 14, 2015

Commentator: Dr. Li-Jin Hsu (徐麗君 教授)             Place: Room 601

Abstract:

    Autophagy is a cellular degradative process by which damaged organelles and intracellular components are encapsulated in double-membrane autophagosomes and then fuse with lysosomes for degradation. Autophagy helps cells respond to stresses, including starvation, and promotes cell survival. The whole mechanism is tightly regulated by autophagy-related proteins (ATGs). LC3 (the microtubule-associated protein 1 light chain 3, a mammalian homolog of yeast Atg8) is an essential regulator of autophagy, which is conjugated to phosphatidylethanolamine (PE) and transported to the preautophagic membrane to form autophagosomes. Despite LC3 mainly functions in the cytoplasm, it also abundantly distributes in the nucleus (1). However, the role of LC3 in the nucleus remains undefined. This paper reveals the essential role of the nuclear LC3 in autophagic machinery. First, the authors observed the nucleocytoplasmic localization of LC3 in different cell types and confirmed the redistribution of nuclear LC3 to cytoplasm during starvation-induced autophagy. They further demonstrated that nuclear LC3 is essential and acts as a primary source of starvation-stimulated autophagosome. According to previous study, LC3 can be deacetylated by nuclear deacetylase Sirt1 (2), and the nuclear protein DOR, a factor involved in cell stress response, interacts with LC3 during the nucleocytoplasmic translocation (3). By performing site-directed mutagenesis and protein-protein interaction analysis, the authors reveals that Sirt1 deactylates LC3 at K49 and K51 and allows the LC3-DOR interaction and the export from the nucleus. The deacetylation is also essential for LC3 to bind ATG7 and other autophagy factors. In conclusion, nuclear LC3 plays an essential role in starvation-induced autophagy, and is regulated by acetylation-deacetylation cycle.

References:

1.         Drake, K.R., Kang, M., and Kenworthy, A.K. (2010). Nucleocytoplasmic distribution and dynamics of the autophagosome marker EGFP-LC3. PLoS One 5, e9806.

2.         Lee, I.H., Cao, L., Mostoslavsky, R., Lombard, D.B., Liu, J., Bruns, N.E., Tsokos, M., Alt, F.W., and Finkel, T. (2008). A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A. 105, 3374-3379.

3.         Nowak, J., Archange, C., Tardivel-Lacombe, J., Pontarotti, P., Pebusque, M.J., Vaccaro, M.I., Velasco, G., Dagorn, J.C., and Iovanna, J.L. (2009). The TP53INP2 protein is required for autophagy in mammalian cells. Mol Biol Cell 20, 870-881.