Hoi1 targets BLTP2 to ER-PM contact sites to regulate lipid homeostasis

Membrane contact sites between organelles are important for maintaining cellular lipid homeostasis. Members of the recently identified family of bridge-like lipid transfer proteins (BLTPs) span apposing membranes at these contact sites to enable the rapid transfer of bulk lipids between organelles. While the VPS13 and ATG2 family members use organelle-specific adaptors for membrane targeting, the mechanisms that regulate other bridge-like transporters are unclear. Here, we identify the conserved protein Ybl086c, which we name Hob interactor 1 (Hoi1), as an adaptor that targets the yeast BLTP2-like proteins Fmp27/Hob1 and Hob2 to ER-plasma membrane (PM) contact sites. Two separate Hoi1 domains interface with α-helical projections that decorate the central hydrophobic channel on Fmp27, and loss of these interactions alters cellular sterol homeostasis. The mutant phenotypes of BLTP2 and HOI1 orthologs indicate these proteins act in a shared pathway in worms and flies. Together, this suggests that Hoi1-mediated recruitment of BLTP2-like proteins represents an evolutionarily conserved mechanism for regulating lipid transport at membrane contact sites.