Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 78, Issue 4, Pages 1689-1708Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-020-03604-w
Keywords
Osh; Sec9; ORP; SNAP-25; SNARE; Membrane contact site
Categories
Funding
- Academy of Finland [257049, 285223, 322647]
- Sigrid Juselius Foundation
- Finnish Foundation for Cardiovascular Research
- Magnus Ehrnrooth Foundation
- Charite Universitatsmedizin Berlin
- Lydia Rabinowitsch-Forderung
- Academy of Finland (AKA) [322647, 285223, 322647] Funding Source: Academy of Finland (AKA)
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OSBP-homologous proteins are lipid binding proteins located at membrane contacts between the endoplasmic reticulum and the plasma membrane. The interactions with secretory SNARE proteins play a crucial role in maintaining lipid metabolism balance and cell function.
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. DeletingOSH1-3in 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.
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