Identification of MOSPD2, a novel scaffold for endoplasmic reticulum membrane contact sites

Membrane contact sites are cellular structures that mediate inter-organelle exchange and communication. The endoplasmic reticulum (ER), which forms a network extending throughout the cytoplasm, possesses two known major tether proteins, named VAP-A and VAP-B, that allow its interaction with other organelles. VAP-A and VAP-B interact with proteins from other organelles that possess a small VAP-interacting motif, named FFAT (two phenylalanines in an acidic track), and consequently scaffold contact sites implicating the ER. In this study, by using an unbiased proteomic approach, we identified a novel ER tether named MOtile SPerm Domain-containing protein 2 (MOSPD2). We showed that MOSPD2 possesses a Motile Sperm Protein (MSP) domain which binds FFAT motifs and consequently allows membrane tethering in vitro. Accordingly, MOSPD2, which is an ER-anchored protein, interacts with several FFAT-containing proteins bound to diverse organelles,such as endosomes, mitochondria or Golgi. Consequently, the specific interaction between MOSPD2 and these organelle-bound proteins results in the formation of contact sites between the ER and these organelles. Thus, MOSPD2 is a novel tether for membrane contact sites between the ER and the other cellular organelles.