title: FXYD5 Protein Has a Pro-inflammatory Role in Epithelial Cells.
abstract: The FXYD proteins are a family of small membrane proteins that share an invariant four amino acid signature motif F-X-Y-D and act as tissue-specific regulatory subunits of the Na,K-ATPase. FXYD5 (also termed dysadherin or RIC) is a structurally and functionally unique member of the FXYD family. As other FXYD proteins, FXYD5 specifically interacts with the Na,K-ATPase and alters its kinetics by increasing Vmax However, unlike other family members FXYD5 appears to have additional functions, which cannot be readily explained by modulation of transport kinetics. Knockdown of FXYD5 in MDA-MB-231 breast cancer cells largely decreases expression and secretion of the chemokine CCL2 (MCP-1). A related effect has also been observed in renal cell carcinoma cells. The current study aims to further characterize the relationship between the expression of FXYD5 and CCL2 secretion. We demonstrate that transfection of M1 epithelial cell line with FXYD5 largely increases lipopolysaccharide (LPS) stimulated CCL2 mRNA and secretion of the translated protein. We have completed a detailed analysis of the molecular events leading to the above response. Our key findings indicate that FXYD5 generates a late response by increasing the surface expression of the TNFα receptor, without affecting its total protein level, or mRNA transcription. LPS administration to mice demonstrates induced secretion of CCL2 and TNFα in FXYD5-expressing lung peripheral tissue, which suggests a possible role for FXYD5 in normal epithelia during inflammation.
authors.affiliation: From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel and irina.lubarski@weizmann.ac.il.
authors.forename: Irina
authors.initials: I
authors.lastname: Lubarski-Gotliv
authors.affiliation: From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel and.
authors.forename: Carol
authors.initials: C
authors.lastname: Asher
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Dada
authors.affiliation: From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel and.
authors.forename: Haim
authors.initials: H
authors.lastname: Garty
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007473:Ion Channels; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C451410:FXYD5 protein, human; C506911:FXYD5 protein, mouse; D018836:Inflammation Mediators; D007473:Ion Channels; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins
keywords: cytokine induction; inflammation; lipopolysaccharide (LPS); plasma membrane; translocation