Hoi1 targets the yeast BLTP2 protein 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 opposing 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 remain unknown. Here, we identify the conserved
protein Ybl086c, which we name Hoi1 (Hob interactor 1), as an adaptor that
targets the yeast BLTP2-like proteins Fmp27/Hob1 and Hob2 to ER-PM contact
sites. Two separate Hoi1 domains interface with alpha-helical projections
that decorate the central hydrophobic channel on Fmp27, and loss of these
interactions disrupts 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.