LC3 is a novel substrate for the mammalian Hippo kinases, STK3/STK4

The Atg8 family protein LC3 is indispensible for autophagy and plays critical roles in multiple steps of the process. Despite this functional significance, the regulation of LC3 activity at the posttranslational level remains poorly understood. In a recent study, we report that the conserved Ste20 kinases STK3 and STK4, the mammalian orthologs of Hippo kinase, are essential for autophagy in diverse organisms, and both can phosphorylate LC3 on amino acid Thr50. STK3/STK4-mediated phosphorylation is critical for fusion of autophagosomes with lysosomes, as well as the ability of cells to clear intracellular bacteria, an established cargo for autophagy. Our discovery of a novel mode of autophagy regulation involving direct phosphorylation of LC3 by STK3/STK4 significantly enhances our molecular understanding of the autophagy process. Moreover, our findings raise the exciting possibility that STK3/STK4's known roles in immunity are exerted through their ability to regulate autophagy via LC3 phosphorylation.