The SAC domain is a lipid polyphosphatase domain conserved in most eukaryotes. It dephosphorylates the headgroup of Phosphatidylinositolphosphates (PIP), a class of phospholipids which is a key regulator of membrane trafficking. The SAC domain was first described in the Yeast lipid phosphatase Sac1p which is a transmembrane protein at the ER and Golgi regulating the amount of PI(4)P. A second SAC domain-containing phosphatase named Fig4p is recruited by adapter proteins to the Yeast vacuole membrane where it converts PI(3,5)P2 to PI(3)P. Both enzymes are essential for membrane trafficking and secretion. In mammalia, the SAC domain is found in the Sac1p homologs SAC1 and SAC2 and in a Fig4p homolog. SAC1 complements the deletion of
sac1 in Yeast. All three proteins are found in neurons, one of which, FIG4 has been implicated in Charcot-Marie-Tooth neuropathies. Like mammals, C. elegans owns two Sac1p homologs F30A10.6 and W09C5.7 and a single Fig4p homolog C34B7.2. F30A10.6 is related to mammalian SAC1 whereas W09C5.7 seems to be the SAC2 ortholog of C. elegans. Thus, the nematode is a perfect model system to study the function of these three lipid phosphatases in higher eukaryotes. C34B7.2 is known to be mainly expressed in the nervous system localizing to synaptic vesicles. RNAi-knockdown causes a decrease in acetylcholine release at neuromuscular junctions. We verified this phenotype for C34B7.2 and in addition also reveal it for F30A10.6. Accordingly, both phosphatases play a role in synaptic vesicle trafficking. In contrast, the knockdown of W09C5.7 did not influence the release of neurotransmitters at neuromuscular junctions. The expression patterns of W09C5.7 and F30A10.6 are unknown. To study functional conservation of the C. elegans phosphatases we expressed HA-tagged proteins in a Yeast
sac1 deletion strain. We show that F30A10.6 can rescue several phenotype characteristics of the Yeast
sac1 knockout, while W09C5.7 and C34B7.2 failed to do so. Consequently, we suggest to change the Accession number F30A10.6 to the gene name
sac-1.