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Abstract
Human lipid phosphatase SAC1 cycles between the ER and Golgi to regulate phosphatidylinositol-4-phosphate (PI4P) distribution. Using a Golgi-targeted SAC1-K2A mutant, we identified two regions controlling Golgi localization: the first transmembrane domain (TM1) and the N-terminal cytoplasmic domain, which also contains a potential oligomerization motif. SAC1-K2A localizes to cis/medial/trans Golgi but not the TGN. Additionally, we discovered 14-3-3 proteins as novel SAC1 interactors, binding a mode II-like motif in the N-terminal domain. Disruption of this interaction impairs ER exit, suggesting phosphorylation-dependent 14-3-3 binding regulates SAC1 trafficking. These findings reveal mechanisms governing SAC1 localization and transport.