An acquired phosphatidylinositol 4-phosphate transport initiates T-cell deterioration and leukemogenesis

Abstract

Lipid remodeling is crucial for malignant cell transformation and tumorigenesis, but the precise molecular processes involved and direct evidences for these in vivo remain elusive. Here, we report that oxysterol-binding protein (OSBP)-related protein 4 L (ORP4L) is expressed in adult T-cell leukemia (ATL) cells but not normal T-cells. In ORP4L knock-in T-cells, ORP4L dimerizes with OSBP to control the shuttling of OSBP between the Golgi apparatus and the plasma membrane (PM) as an exchanger of phosphatidylinositol 4-phosphate [PI(4)P]/cholesterol. The PI(4)P arriving at the PM via this transport machinery replenishes phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and phosphatidylinositol (3,4,5) trisphosphate [PI(3,4,5)P3] biosynthesis, thus contributing to PI3K/AKT hyperactivation and T-cell deterioration in vitro and in vivo. Disruption of ORP4L and OSBP dimerization disables PI(4)P transport and T-cell leukemogenesis. In summary, we identify a non-vesicular lipid transport machinery between Golgi and PM maintaining the oncogenic signaling competence initiating T-cell deterioration and leukemogenesis.

Essential Domains of Oxysterol-Binding Protein Required for Poliovirus Replication

“…Interestingly, the ∆180-349 and ∆180-360 variants, both of which lack the dimerization domain, showed partial localization at the plasma membrane in the HEK293 cells (Figure 2 and Figure S2). Localization of OSBP at the plasma membrane requires dimerization with OSBP2 in OSBP2-knock-in T cells [16], in contrast to the above observations in the HEK293 cells. Factors that could affect subcellular localization of OSBP remain to be elucidated, but the CCR seemed not essential for the targeting to the RO in the infected cells (Figure 2).…”

“…OSBP (GenBank: NM_002556, 807 amino acid residues), which was originally identified as a high-affinity receptor for oxysterol, [10], acts as an exchanger of cholesterol/ phosphatidylinositol 4-monophosphate (PI4P) [11,12], resulting in transport of cholesterol from endoplasmic reticulum (ER) to the trans Golgi [12] and to lysosomes for rapid lysosomal repair [13,14] and from recycling endosomes to the trans Golgi [15]. OSBP could transport PI4P to the plasma membrane via dimerization with OSBP2 in T cells [16].…”

Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP

“…Supported by OSBP rescue data, we hence surmise that the antiproliferative consequences of orpinolide are conveyed by OSBP inhibition, even though we cannot rule out the contribution of additional factors at high orpinolide concentrations. Notably, through orchestrating the transport of PI4P between the ER and the plasma membrane, several members of the ORP family, including OSBP, have been shown to sustain hyperactive PI3K/AKT signaling 55,56 , a known vulnerability in leukemia cells, especially T cell-derived ALL cell lines 57,58 . Indeed, cellular treatment with orpinolide led to attenuated AKT signaling, thus providing a mechanistic rationale for its antileukemic activity.…”

Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP

“…45 Akin to OSBP, ORP4 is also thought to orchestrate the transport of PI4P between the ER and the plasma membrane, thereby supporting hyperactivity of the PI3K/AKT pathway and leukemogenesis of T cells. 49 Initially, these observations provided an intriguing hypothesis for the observed anti-leukemic efficacy of orpinolide as a selective, dual inhibitor of OSBP/ORP4. Arrayed gene disruption experiments of OSBP and ORP4, either individually or in combination, however, clearly indicate that OSBP represents the predominant dependency.…”