The emerging roles of OSBP-related proteins in cancer : Impacts through phosphoinositide metabolism and protein-protein interactions

Oxysterol-binding protein-related proteins (ORPs) form a large family of intracellular lipid binding/transfer proteins. A number of ORPs are implicated in inter-organelle lipid transfer over membrane contacts sites, their mode of action involving in several cases the transfer of two lipids in opposite directions, termed countercurrent lipid transfer. A unifying feature appears to be the capacity to bind phosphatidylinositol polyphosphates (PIPs). These lipids are in some cases transported by ORPs from one organelle to another to drive the transfer of another lipid against its concentration gradient, while they in other cases may act as allosteric regulators of ORPs, or an ORP may introduce a PIP to an enzyme for catalysis. Dysregulation of several ORP family members is implicated in cancers, ORP3,-4,-5 and-8 being thus far the most studied examples. The most likely mechanisms underlying their associations with malignant growth are (i) impacts on PIP-mediated signaling events resulting in altered Ca2+ homeostasis, bioenergetics, cell survival, proliferation, and migration, (ii) protein-protein interactions affecting the activity of signaling factors, and (iii) modification of cellular lipid transport in a way that facilitates the proliferation of malignant cells. In this review I discuss the existing functional evidence for the involvement of ORPs in cancerous growth, discuss the findings in the light of the putative mechanisms outlined above and the possibility of employing ORPs as targets of anti-cancer therapy.Peer reviewe

Protrudin in protrudinG invadopodia : Membrane contact sites and cell invasion

Invadopodia are dynamic protrusions that harbor matrix metalloproteinases for pericellular matrix degradation. However, the mechanisms underlying their maturation are poorly understood. Pedersen et al. (2020. J. Cell Biol. https://doi.org/10.1083/jcb.202003063) demonstrate a dual role of Protrudin in invadopodia elongation and matrix degradation, central to cell invasion and cancer metastasis.Non peer reviewe

In memoriam : Christian Ehnholm

Non peer reviewe

Oxysterols and Their Cellular Effectors

Oxysterols are oxidized 27-carbon cholesterol derivatives or by-products of cholesterol biosynthesis, with a spectrum of biologic activities. Several oxysterols have cytotoxic and pro-apoptotic activities, the ability to interfere with the lateral domain organization, and packing of membrane lipids. These properties may account for their suggested roles in the pathology of diseases such as atherosclerosis, age-onset macular degeneration and Alzheimer’s disease. Oxysterols also have the capacity to induce inflammatory responses and play roles in cell differentiation processes. The functions of oxysterols as intermediates in the synthesis of bile acids and steroid hormones, and as readily transportable forms of sterol, are well established. Furthermore, their actions as endogenous regulators of gene expression in lipid metabolism via liver X receptors and the Insig (insulin-induced gene) proteins have been investigated in detail. The cytoplasmic oxysterol-binding protein (OSBP) homologues form a group of oxysterol/cholesterol sensors that has recently attracted a lot of attention. However, their mode of action is, as yet, poorly understood. Retinoic acid receptor-related orphan receptors (ROR) α and γ, and Epstein-Barr virus induced gene 2 (EBI2) have been identified as novel oxysterol receptors, revealing new physiologic oxysterol effector mechanisms in development, metabolism, and immunity, and evoking enhanced interest in these compounds in the field of biomedicine.Peer reviewe

New medications targeting triglyceride-rich lipoproteins: Can inhibition of ANGPTL3 or apoC-III reduce the residual cardiovascular risk?

Remarkably good results have been achieved in the treatment of atherosclerotic cardiovascular diseases (CVD) by using statin, ezetimibe, antihypertensive, antithrombotic, and PCSK9 inhibitor therapies and their proper combinations. However, despite this success, the remaining CVD risk is still high. To target this residual risk and to treat patients who are statin-intolerant or have an exceptionally high CVD risk for instance due to familial hypercholesterolemia (FH), new therapies are intensively sought. One pathway of drug development is targeting the circulating triglyceride-rich lipoproteins (TRL) and their lipolytic remnants, which, according to the current view, confer a major CVD risk. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are at present the central molecular targets for therapies designed to reduce TRL, and there are new drugs emerging that suppress their expression or inhibit the function of these two key proteins. The medications targeting these components are biological, either human monoclonal antibodies or antisense oligonucleotides. In this article, we briefly review the mechanisms of action of ANGPTL3 and apoC-III, the reasons why they have been considered promising targets of novel therapies for CVD, as well as the current status and the most important results of their clinical trials. (C) 2018 Elsevier B.V. All rights reserved.Peer reviewe

Coordination of inter-organelle communication and lipid fluxes by OSBP-related proteins

Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) constitute one of the largest families of lipid-binding/transfer proteins (LTPs) in eukaryotes. The current view is that many of them mediate interorganelle lipid transfer over membrane contact sites (MCS). The transfer occurs in several cases in a 'countercurrent' fashion: A lipid such as cholesterol or phosphatidylserine (PS) is transferred against its concentration gradient driven by transport of a phosphoinositide in the opposite direction. In this way ORPs are envisioned to maintain the distinct organelle lipid compositions, with impacts on multiple organelle functions. However, the functions of ORPs extend beyond lipid homeostasis to regulation of processes such as cell survival, proliferation and migration. Important expanding areas of mammalian ORP research include their roles in viral and bacterial infections, cancers, and neuronal function. The yeast OSBP homologue (Osh) proteins execute multifaceted functions in sterol and glycerophospholipid homeostasis, post-Golgi vesicle transport, phosphatidylinositol-4-phosphate, sphingolipid and target of rapamycin (TOR) signalling, and cell cycle control. These observations identify ORPs as lipid transporters and coordinators of signals with an unforeseen variety of cellular processes. Understanding their activities not only enlightens the biology of the living cell but also allows their employment as targets of new therapeutic approaches for disease.Peer reviewe

OSBP-Related Proteins: Liganding by Glycerophospholipids Opens New Insight into Their Function

Peer reviewe