A Detour for Yeast Oxysterol Binding Proteins

Abstract

Oxysterol binding protein-related proteins, including the yeast proteins encoded by the OSH gene family (OSH1-OSH7), are implicated in the non-vesicular transfer of sterols between intracellular membranes and the plasma membrane. In light of recent studies, we revisited the proposal that Osh proteins are sterol transfer proteins and present new models consistent with known Osh protein functions. These models focus on the role of Osh proteins as sterol-dependent regulators of phosphoinositide and sphingolipid pathways. In contrast to their posited role as non-vesicular sterol transfer proteins, we propose that Osh proteins coordinate lipid signaling and membrane reorganization with the assembly of tethering complexes to promote molecular exchanges at membrane contact sites.

Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing

“…27 Since OSBP was first identified in the mid-1980s by Taylor et al 29 as a soluble, high-affinity receptor, evidence has accumulated indicating that the OSBP/ORP family plays important roles in regulating cellular lipid homeostasis and in many cellular processes, including cell signaling, vesicular trafficking, lipid metabolism, and particularly sterol signaling or sterol transport functions. [30][31][32] OSBPL2 (ORP2) is a member of the OSBP/ORP family and is also the only mammalian isoform that is expressed exclusively as a truncated short ORP lacking the pleckstrin homology and Golgi dynamics domains, which are found in other OSBP/ORP family members, but harboring a FFAT (two phenylalanines in an acidic tract) motif and an ORD region (Figure 2e). It is known that a common feature of all ORPs is the conserved C-terminal ORD.…”

“…It is known that a common feature of all ORPs is the conserved C-terminal ORD. 30,31 Tong et al 32 proved that the unifying role in all ORP homologs was the binding of PI [4]P to ORD, with additional sterol binding for certain homologs, and yeast complementation tests showed that PI [4]P binding to ORD is essential for function. A strictly conserved OSBP-fingerprint motif, "EQVSHHPP, " in the ORD region of OSBPL2 is a specific binding motif for the head of the group of the PI[4]P ligand, suggesting roles as phosphoinositide-binding proteins [20][21][22] (Figure 2e).…”

Nonvesicular Lipid Transfer from the Endoplasmic Reticulum

“…Yet, the function of its sterolbinding/transfer activity is not completely understood. Although it is possible that Osh4p functions as a PI4P/sterol-exchange protein (de Saint-Jean et al 2011), recent studies suggest that sterols are inhibitory ligands of Osh4p activity, and not transported cargo (Beh et al 2012). Regardless of the specific role of sterols as transported cargo or inhibitory ligands, it is clear that the dual lipid-binding capability of Osh4 promotes coordinated distribution of phosphoinositides and sterols between cellular membranes.…”

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

“…Osh3p belongs to a family of oxysterol-binding proteins; yeast cells have seven OSH homologs (28). Previous work showed that oxysterol-binding protein homolog 2 (OSH2) overexpression also could rescue α-synFL (17).…”