Function of Nat9 acetyltransferase in microtubule stability, JNK signaling and Hippo pathway in drosophila

Abstract

Regulation of microtubule stability is crucial for the maintenance of cell structure and function. Recent studies suggest that microtubules are also involved in cell signaling, but the underlying mechanisms are largely unknown. Here we show that a Drosophila homolog of human N-terminal acetyltransferase 9 (Nat9, CG11539) is essential for organ development by stabilizing microtubules. Reduced Nat9 causes severe developmental defects in different organs by inducing apoptotic cell death. Depletion of Nat9 in imaginal discs increases the level of phosphorylated JNK (pJNK), as a cause of cell death. Reduced JNK signaling components suppresses cell death and restores Nat9 RNAi phenotypes. We found that Nat9 co-localizes with microtubules in tissues and is physically associated with microtubules in vitro and in vivo. Overexpression of Nat9 enhances the stability of microtubule while its loss causes mitotic spindle defects. We show that Nat9 can acetylate the N-termini of both alpha and beta tubulin in vitro. Function of human Nat9 has not been characterized. We demonstrate that human Nat9 can rescue Nat9 RNAi phenotypes in flies, indicating their functional conservation. Further experiments revealed the relationship between Nat9 and Hippo signaling pathway. Knockdown of Nat9 rescues overproliferation phenotypes induced by upregulated Yki activity. Physical interactions between Mer and Nat9 as well as Tao1 and Nat9 were also identified. Downregulation of Nat9 suppresses Yki activity. This study suggests that Nat9 is crucial for stabilizing microtubules and that the stabilized microtubules inhibits JNK signaling to promote cell survival in developing organs and regulates Yki activity as well.