title: Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions.
abstract: In vitro studies have demonstrated that occludin and tricellulin are important for tight junction barrier function, but in vivo data suggest that loss of these proteins can be overcome. The presence of a heretofore unknown, yet related, protein could explain these observations. Here, we report marvelD3, a novel tight junction protein that, like occludin and tricellulin, contains a conserved four-transmembrane MARVEL (MAL and related proteins for vesicle trafficking and membrane link) domain. Phylogenetic tree reconstruction; analysis of RNA and protein tissue distribution; immunofluorescent and electron microscopic examination of subcellular localization; characterization of intracellular trafficking, protein interactions, dynamic behavior, and siRNA knockdown effects; and description of remodeling after in vivo immune activation show that marvelD3, occludin, and tricellulin have distinct but overlapping functions at the tight junction. Although marvelD3 is able to partially compensate for occludin or tricellulin loss, it cannot fully restore function. We conclude that marvelD3, occludin, and tricellulin define the tight junction-associated MARVEL protein family. The data further suggest that these proteins are best considered as a group with both redundant and unique contributions to epithelial function and tight junction regulation.
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Raleigh
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Marchiando
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Le
authors.initials: L
authors.lastname: Shen
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasaki
authors.forename: Yingmin
authors.initials: Y
authors.lastname: Wang
authors.forename: Manyuan
authors.initials: M
authors.lastname: Long
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018938:Caco-2 Cells; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D062794:MARVEL Domain Containing 2 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence / Q000379:methods; D016253:Microscopy, Immunoelectron / Q000379:methods; D008969:Molecular Sequence Data; D062793:Occludin; D010802:Phylogeny; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D013347:Subcellular Fractions / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D062794:MARVEL Domain Containing 2 Protein; C516798:MARVELD2 protein, human; C548163:MARVELD3 protein, human; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse