Phosphorylation by casein kinase 2 induces PACS-1 binding of nephrocystin and targeting to cilia.
Mutations in proteins localized to cilia and basal bodies have been implicated in a growing number of human diseases. Access of these proteins to the ciliary compartment requires targeting to the base of the cilia. However, the mechanisms involved in transport of cilia proteins to this transitional zone are elusive. Here we show that nephrocystin, a ciliary protein mutated in the most prevalent form of cystic kidney disease in childhood, is expressed in respiratory epithelial cells and accumulates at the base of cilia, overlapping with markers of the basal body area and the transition zone. Nephrocystin interacts with the phosphofurin acidic cluster sorting protein (PACS)-1. Casein kinase 2 (CK2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates PACS-1 binding, and is essential for colocalization of nephrocystin with PACS-1 at the base of cilia. Inhibition of CK2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting. These data suggest that CK2-dependent transport processes represent a novel pathway of targeting proteins to the cilia.
Schermer
Bernhard
B
Renal Division, University Hospital Freiburg, Freiburg, Germany.
Höpker
Katja
K
Omran
Heymut
H
Ghenoiu
Cristina
C
Fliegauf
Manfred
M
Fekete
Andrea
A
Horvath
Judit
J
Köttgen
Michael
M
Hackl
Matthias
M
Zschiedrich
Stefan
S
Huber
Tobias B
TB
Kramer-Zucker
Albrecht
A
Zentgraf
Hanswalter
H
Blaukat
Andree
A
Walz
Gerd
G
Benzing
Thomas
T
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D047390:Casein Kinase II / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002923:Cilia / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D013997:Time Factors; D014132:Trachea / Q000378:metabolism; D014162:Transfection; D033921:Vesicular Transport Proteins
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C108725:NPHP1 protein, human; C491914:PACS1 protein, human; D011506:Proteins; D033921:Vesicular Transport Proteins; D012694:Serine; D047390:Casein Kinase II