{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPLEKHA8 (also known as FAPP2) is an essential lipid‐transfer protein that orchestrates post‐Golgi membrane trafficking and the organization of specialized plasma membrane domains. It functions by binding phosphatidylinositol 4‐phosphate via its pleckstrin homology domain and cooperating with small GTPases (e.g., ARF1) to facilitate the generation and fission of transport carriers from the trans‐Golgi network, thereby regulating apical cargo transport and ciliogenesis in polarized epithelial cells. In addition, FAPP2 couples its lipid transfer activity to glycosphingolipid metabolism, ensuring that newly synthesized glucosylceramide is efficiently delivered to the plasma membrane to maintain lipid identity and support the formation of condensed apical domains."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and mechanistic studies have further illuminated the dual lipid‐binding nature of PLEKHA8. Crystallographic and scattering analyses reveal that FAPP2 forms a curved, dimeric assembly capable of remodeling membranes into tubules—a process dependent on both its phosphoinositide-binding and glycolipid-transfer domains. This dual functionality is exploited during viral infection, as exemplified by hepatitis C virus replication; here, FAPP2 is recruited to the viral replication complex by PI4P and functions to deliver glycosphingolipids that are crucial for RNA synthesis, highlighting its pivotal role in pathogen-host interactions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in membrane trafficking and lipid metabolism, alterations in PLEKHA8 expression have been implicated in various pathophysiological conditions, including tumorigenesis and pregnancy disorders. In cancer models, modulation of FAPP2 levels influences cell survival and proliferation—its downregulation sensitizes tumor cells to apoptosis and disrupts oncogenic signaling (for example, via the Wnt/β-catenin pathway), as seen in studies of colon carcinoma, hepatocellular carcinoma, and T-cell acute lymphoblastic leukemia. Similarly, in reproductive contexts, miR-98–mediated repression of FAPP2 is linked to impaired trophoblast proliferation in cases of missed abortion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Anna Godi, Antonella Di Campli, Athanasios Konstantakopoulos, et al. 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