Multiple interactions recruit BLTP2 to ER-PM contacts to control plasma membrane dynamics.

BLTP2/KIAA0100, a bridge-like lipid transfer protein, was reported to localize at contacts of the ER with either the plasma membrane (PM) or recycling tubular endosomes depending on the cell type. Our findings suggest that mediating bulk lipid transport between the ER and the PM is a key function of this protein, as BLTP2 tethers the ER to tubular endosomes only after they become continuous with the PM and that it also tethers the ER to macropinosomes in the process of fusing with the PM. We further identify interactions underlying binding of BLTP2 to the PM, including phosphoinositides, the adaptor proteins FAM102A/FAM102B, and N-BAR domain proteins at membrane-connected tubules. The absence of BLTP2 results in the accumulation of intracellular vacuoles, many of which are connected to the PM, pointing to a role of the lipid transport function of BLTP2 in the control of PM dynamics.