A mutation in VAPB causes a familial form of Amyotrophic Lateral Sclerosis. The mutant protein (VAPB-P56S) is aggregate prone and blocks retrograde traffic from the endoplasmic reticulum (ER) Golgi intermediate compartment (ERGIC) including trafficking to the nuclear envelope (NE). Here we report a morphological screen where overexpression of oxysterol binding protein-related protein-3 (ORP3) rescued the mutant VAPB phenotype. It resolved the mutant VAPB-induced membrane expansions, restored solubility of the mutant protein in non-ionic detergent, and restored trafficking of Emerin to the NE. Knockdown of ORP3 or VAPB increased the intracellular level of phosphatidylinositol 4-phosphate (PtdIns4P). Decreasing PtdIns4P levels by inhibiting its synthesis reduced the severity of the mutant VAPB-induced membrane expansions and restored Emerin trafficking to the NE. Thus, VAPB and its interacting partners cooperatively regulate protein trafficking through the ERGIC by modulating PtdIns4P levels.