ORP/Osh mediate cross-talk between ER-plasma membrane contact site components and plasma membrane SNAREs

• Published in: Cellular and molecular life sciences : CMLS 2021-02, Vol.78 (4), p.1689-1708
• Main Authors: Weber-Boyvat, Marion, Trimbuch, Thorsten, Shah, Saundarya, Jäntti, Jussi, Olkkonen, Vesa M., Rosenmund, Christian
• Format: Article
• Language: English
• Subjects: Animals; Binding; Biochemistry; Biological Transport - genetics; Biomedical and Life Sciences; Biomedicine; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Biology; Cell Membrane - genetics; Cell Membrane - metabolism; Crosstalk; Endoplasmic reticulum; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Exocytosis; Exocytosis - genetics; Homology; Humans; Life Sciences; Lipid Metabolism - genetics; Lipids; Membrane Proteins - genetics; Membranes; Mice; Neurons; Oligomerization; Original; Original Article; Plasma; Proteins; Qc-SNARE Proteins - genetics; Receptors, Steroid - genetics; Regulators; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; SNAP receptors; SNAP-25 protein; SNARE Proteins - genetics; Sterols - metabolism; Synaptosomal-Associated Protein 25 - genetics; Vesicular Transport Proteins - genetics; Yeast; Yeasts
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-020-03604-w

OSBP-homologous proteins (ORPs, Oshp) are lipid binding/transfer proteins. Several ORP/Oshp localize to membrane contacts between the endoplasmic reticulum (ER) and the plasma membrane, where they mediate lipid transfer or regulate lipid-modifying enzymes. A common way in which they target contacts is by binding to the ER proteins, VAP/Scs2p, while the second membrane is targeted by other interactions with lipids or proteins. We have studied the cross-talk of secretory SNARE proteins and their regulators with ORP/Oshp and VAPA/Scs2p at ER-plasma membrane contact sites in yeast and murine primary neurons. We show that Oshp-Scs2p interactions depend on intact secretory SNARE proteins, especially Sec9p. SNAP-25/Sec9p directly interact with ORP/Osh proteins and their disruption destabilized the ORP/Osh proteins, associated with dysfunction of VAPA/Scs2p. Deleting OSH1-3 in yeast or knocking down ORP2 in primary neurons reduced the oligomerization of VAPA/Scs2p and affected their multiple interactions with SNAREs. These observations reveal a novel cross-talk between the machineries of ER-plasma membrane contact sites and those driving exocytosis.