Role of Lipid Transfer Proteins (LTPs) in the Viral Life Cycle

Figures

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  FIGURE 1. Schematic illustration of the protein domains in the respective lipid transfer proteins. The (red boxes) represent the Pleckstrin homology domain (PH domain) which binds to phosphatidylinositol-4-phosphate (PI4P) that is commonly present in OSBP, CERT, and FAPP. The FFAT motif which promotes interaction with ER-resident VAP proteins is represented in (green box) is present in OSBP, CERT, and STARD proteins. STEROL binding domain (dark yellow box), START domain (navy blue box), GLTP domain (gray box), and SMP domain (purple box) represents the characteristic lipid-binding domains specific for the individual LTPs. START proteins also have a multifunctional MENTAL domain (violet box) that binds to cholesterol. The E-Syts transfers glycerophospholipids through its mitochondrial-lipid-binding protein domain (SMP) (purple box). The E-Syts protein has a variable number of C2 domains (pine green boxes) which is responsible for Ca2+/phospholipid binding and protein–protein interactions. NPC1 has a cholesterol binding domain NTD (brown box), sterol sensing domain (SSD) (bottle green box) and a Cystine rich C terminal domain (dark gray box). Unlike NPC1, NPC2 consists of a signal peptide…

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  FIGURE 2. Schema representing the role of lipid transfer proteins in HCV life cycle. HCV virus gains entry via receptor-mediated endocytosis and subsequent uncoating of the viral envelope in the endocytic vesicles results in the release of viral genome into the cytoplasm. The viral RNA gets translated on the rough ER leading to the biosynthesis of viral polyprotein that is subsequently processed by host and viral proteases to yield structural and non-structural viral proteins. Viral proteins along with other host factors promote the rearrangement of ER-derived membranes to establish the viral replication complex. Recruitment and activation of PI4KIIIα at viral replication sites leads to enhanced levels of phosphatidylinositol-4-phosphate (PI4P) at replication sites resulting in recruitment of the lipid transfer proteins OSBP and CERT to the membranes. OSBP and CERT bind to PI4P via their Pleckstrin homology (PH) domains and to the ER anchored vesicle-associated membrane-associated protein (VAP) by FFAT motif. Both OSBP and CERT bind to their respective lipid ligands (i.e., cholesterol or ceramide) through their lipid binding domains and catalyze the transfer of cholesterol and ceramide…

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  FIGURE 3. Schematic summary of the lipid transfer proteins as attractive therapeutic avenues against viruses. OSW1, ITZ (Itraconazole), POS (Posaconazole) binds to OSBP and inhibits its lipid shuttling activity at the ER-Golgi or ER-Viral replication membrane contact sites resulting in the disruption of viral replication sites. HPA-12 is a CERT inhibitor that inhibits ceramide trafficking from the ER to the site of sphingomyelin synthesis. PIK93 can inhibit both PI4KIIIα and PI4KIIIβ whereas AL9 inhibits PI4KIIIα thereby inhibiting PI4P production and recruitment of OSBP and CERT, which eventually affects non-vesicular lipid transport and viral replication sites integrity. U18666A binds to the luminal loop of NPC1 and blocks NPC1 mediated cholesterol flux from late endosomes/lysosomes thereby affecting viral entry and release into the cytosol (Created with BioRender.com).