Oxysterol-binding protein (OSBP) and the OSBP-Related proteins (ORPs) constitute an evolutionarily conserved protein superfamily found in all eukaryotic organisms. The cellular functions of the 12 human OSBP/ORP are not fully understood, but these proteins have been implicated in lipid transport and/or lipid regulation activities. Two members of this protein family, OSBP and ORP4, have been implicated in human disease. OSBP is a ubiquitously expressed protein in all tissues that was recently discovered to be essential in replication of many type of viruses. In contrast, ORP4 is only normally expressed in a few types of tissues. ORP4 has recently been reported to be essential for cancer cell survival and proliferation, particularly in certain forms of leukemia. The natural product compound OSW-1 is known to be a high affinity ligand for both OSBP and ORP4, and through binding to these proteins, OSW-1 demonstrates anti-proliferative and anti-viral properties. We used the OSW-1-compound as a chemical probe to better define the cellular function of both OSBP and ORP4 protein functions. We discovered that OSBP and ORP4 cellular protein levels can be regulated by the OSW-1-compound through an unusual method of protein repression. Additionally, we determined that the OSBP protein is involved in cellular nutritional sensing and regulation. These results indicate an endogenous regulation system exists in cells to alter OSBP and ORP4 activity and expression levels upon binding to specific ligands.

Cellular effects of ligand binding to the Oxysterol-binding protein family (OSBP/ORP4)

255th National Meeting (2018)

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