{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nOccludin is a multispan transmembrane protein that is a core component of tight junctions, which critically regulate paracellular permeability and maintain epithelial and endothelial barrier integrity. Structural studies and dynamic imaging have revealed that occludin’s C‐terminal domain, its alternatively spliced isoforms, and its ability to engage in rapid membrane exchange underpin its function in tight junction assembly and regulation. These analyses, together with biochemical investigations into its extracellular loop interactions, underscore its role as a scaffold that coordinates binding to partners such as ZO‐1 while undergoing regulated post‐translational modifications."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSeveral studies have identified occludin as an essential host factor for viral entry. In the context of hepatitis C virus (HCV) infection, occludin works in concert with other tight junction proteins—such as claudin‐1 and CD81—to enable the virus to enter target cells, and its species‐specific determinants are critical for infectivity. In addition, occludin is actively internalized during infection by viruses like coxsackievirus, a process necessary for efficient viral uptake."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOccludin is also subject to extensive regulation by intracellular signaling pathways that modulate its phosphorylation state and subcellular distribution, thereby dynamically controlling tight junction permeability. Oxidative stress, cytokines, and growth factors can trigger specific kinase activities—including those of ERK, CK2, PKC η, and c‐Src—that alter occludin’s tyrosine and serine/threonine phosphorylation, weakening its interactions with ZO‐1 and promoting its internalization or redistribution. Such modifications have been implicated in blood–brain barrier breakdown in inflammatory and neurodegenerative conditions, as well as in vascular leakage induced by amyloid‐β or HIV‐1 Tat. In these settings, additional factors such as matrix metalloproteinases and RhoA/ROCK signaling further contribute to occludin degradation and barrier dysfunction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its fundamental role in barrier maintenance, alterations in occludin expression and localization contribute to disease pathogenesis, including tumor progression, epithelial‐to‐mesenchymal transition (EMT), and inflammation. Loss of occludin, whether by transcriptional repression via factors such as Snail or Slug or through post‐translational modifications, is associated with increased invasiveness in various carcinomas and is observed in conditions such as psoriasis and hepatocellular carcinoma. Moreover, occludin has been implicated in cell polarity and directional migration, with its deregulation contributing to abnormal tissue organization and metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional evidence highlights the involvement of occludin in epithelial differentiation. In cultured keratinocytes, for instance, occludin localization is coordinated with the assembly of functional tight junctions that contribute to barrier formation in the skin. This differentiation-dependent regulation helps maintain tissue homeostasis under both normal and inflammatory conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "42"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Emily Steed, Nelio T L Rodrigues, Maria S Balda, et al. 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