Identification of Palmitoyltransferase and Thioesterase Enzymes that Control the Subcellular Localisation of Axon Survival Factor Nicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2) [Cell Biology]
September 30th, 2014 by Milde, S., Coleman, M. P.
The NAD-synthesising enzyme NMNAT2 is a critical survival factor for axons and its constant supply from neuronal cell bodies into axons is required for axon survival in primary culture neurites and for axon extension in vivo. Recently, we showed that palmitoylation is necessary to target NMNAT2 to post-Golgi vesicles, thereby influencing its protein turnover and axon protective capacity. Here we find that NMNAT2 is a substrate for the cytosolic thioesterases APT1 and APT2 and that palmitoylation/depalmitoylation dynamics are on a timescale similar to its short half-life. Interestingly, however, depalmitoylation does not release NMNAT2 from membranes. The mechanism of palmitoylation-independent membrane attachment appears to be mediated by the same minimal domain required for palmitoylation itself. Furthermore, we identify several zDHHC palmitoyltransferases that influence NMNAT2 palmitoylation and subcellular localisation, among which a role for zDHHC17 (HIP14) in neuronal NMNAT2 palmitoylation is best supported by our data. These findings shed light on the enzymatic regulation of NMNAT2 palmitoylation and highlight individual thioesterases and palmitoyltransferases as potential targets to modulate NMNAT2-dependent axon survival.