{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTricellulin, encoded by MARVELD2, is a core tight junction protein that localizes predominantly at tricellular contacts—where the corners of three cells converge—as well as along bicellular junctions. As a member of the MARVEL protein family, it works in concert with related proteins such as occludin and marvelD3 to control paracellular permeability, thereby maintaining barrier integrity by regulating the passage of ions and macromolecules. Its selective distribution and contribution to strand linearity at tight junctions emphasize its role as a molecular “gatekeeper” in diverse epithelia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTricellulin’s function is dynamically regulated by diverse signaling mechanisms. It undergoes phosphorylation by serine/threonine kinases and is modulated by pathways such as JNK and PKC; these modifications affect its localization and barrier properties during tight junction assembly and remodeling (e.g., in response to extracellular calcium shifts). In addition, tricellulin is subject to posttranslational regulation via ubiquitination by the E3 ubiquitin ligase Itch, and its expression can be downregulated by inflammatory cytokines such as interleukin-13. Such layers of regulation coordinate its trafficking and function to preserve epithelial integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nLoss‐of‐function mutations in MARVELD2 have been directly implicated in autosomal recessive non‐syndromic hearing loss. Disruption of tricellulin reduces the integrity of tricellular tight junctions in the inner ear, leading to impaired barrier function and consequent auditory deficits. Clinical studies in diverse populations have identified recurrent mutations in this gene, which underscore its critical role in auditory physiology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its essential role in hearing, tricellulin is a pivotal component of epithelial barrier function in many organs. Its expression has been documented in diverse tissues—including nasal epithelia, pancreatic and hepatic cells, brain endothelium, and even cells of the immune system such as microglia—where alterations in its abundance or localization are associated with pathological conditions. For instance, aberrant tricellulin distribution correlates with changes in paracellular ion conductance, increased macromolecular permeability, and has been linked to tumor progression in pancreatic, hepatic, and colorectal cancers, as well as to microbial exploitation during epithelial invasion. Collectively, these observations highlight the broad impact of MARVELD2 function (and dysfunction) on tissue homeostasis and disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Susanne M Krug, Salah Amasheh, Jan F Richter, et al. 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