miR-14 Regulates Autophagy during Developmental Cell Death by Targeting ip3-kinase 2

Macroautophagy (autophagy) is a lysosome-dependent degradation process that has been implicated in age-associated diseases. Autophagy is involved in both cell survival and cell death, but little is known about the mechanisms that distinguish its use during these distinct cell fates. Here, we identify the microRNA miR-14 as being both necessary and sufficient for autophagy during developmentally regulated cell death in Drosophila. Loss of miR-14 prevented induction of autophagy during salivary gland cell death, but had no effect on starvation-induced autophagy in the fat body. Moreover, misexpression of miR-14 was sufficient to prematurely induce autophagy in salivary glands, but not in the fat body. Importantly, miR-14 regulates this context-specific autophagy through its target, inositol 1,4,5-trisphosphate kinase 2 (ip3k2), thereby affecting inositol 1,4,5-trisphosphate (IP3) signaling and calcium levels during salivary gland cell death. This study provides in vivo evidence of microRNA regulation of autophagy through modulation of IP3 signaling. [Display omitted] •miR-14 is necessary and sufficient for autophagy during cell death•miR-14 targets the inositol 1,4,5-trisphosphate kinase 2 gene to regulate autophagy•IP3 signaling and Calmodulin are necessary for autophagy during cell death•miR-14 regulates calcium levels during salivary gland destruction miR-14 has previously been shown to modulate caspase activity and hormone signaling. Nelson et al. show that miR-14 does not modulate either of these processes during salivary gland cell death. Rather, it regulates autophagy through control of calcium signaling.