title: OFD1 and flotillins are integral components of a ciliary signaling protein complex organized by polycystins in renal epithelia and odontoblasts.
abstract: Mutation of the X-linked oral-facial-digital syndrome type 1 (OFD1) gene is embryonic lethal in males and results in craniofacial malformations and adult onset polycystic kidney disease in females. While the OFD1 protein localizes to centriolar satellites, centrosomes and basal bodies, its cellular function and how it relates to cystic kidney disease is largely unknown. Here, we demonstrate that OFD1 is assembled into a protein complex that is localized to the primary cilium and contains the epidermal growth factor receptor (EGFR) and domain organizing flotillin proteins. This protein complex, which has similarity to a basolateral adhesion domain formed during cell polarization, also contains the polycystin proteins that when mutant cause autosomal dominant polycystic kidney disease (ADPKD). Importantly, in human ADPKD cells where mutant polycystin-1 fails to localize to cilia, there is a concomitant loss of localization of polycystin-2, OFD1, EGFR and flotillin-1 to cilia. Together, these data suggest that polycystins are necessary for assembly of a novel flotillin-containing ciliary signaling complex and provide a molecular rationale for the common renal pathologies caused by OFD1 and PKD mutations.
authors.affiliation: Department of Pathology MSC08-4640 and Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jerman
authors.affiliation: Department of Internal Medicine, Division of Nephrology MSC10-5550, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Ward
authors.affiliation: Department of Pathology MSC08-4640 and Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, United Kingdom.
authors.forename: Carla A M
authors.initials: CA
authors.lastname: Lopes
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, United Kingdom.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Fry
authors.affiliation: Institute of Oral Health Research & Department of Oral and Maxillofacial Surgery, School of Dentistry, University of Alabama, Birmingham, Alabama, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: MacDougall
authors.affiliation: Department of Pathology MSC08-4640 and Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Wandinger-Ness
mesh_terms: D000328:Adult; D002460:Cell Line; D002923:Cilia / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009804:Odontoblasts / Q000378:metabolism*; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000378:metabolism*
chemical_list: D066246:ErbB Receptors; D049452:Green Fluorescent Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D050505:Mutant Proteins; D011506:Proteins; D050396:TRPP Cation Channels; C115130:OFD1 protein, human; C106354:flotillins