Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation.
The trafficking of ion channels to the plasma membrane is tightly controlled to ensure the proper regulation of intracellular ion homeostasis and signal transduction. Mutations of polycystin-2, a member of the TRP family of cation channels, cause autosomal dominant polycystic kidney disease, a disorder characterized by renal cysts and progressive renal failure. Polycystin-2 functions as a calcium-permeable nonselective cation channel; however, it is disputed whether polycystin-2 resides and acts at the plasma membrane or endoplasmic reticulum (ER). We show that the subcellular localization and function of polycystin-2 are directed by phosphofurin acidic cluster sorting protein (PACS)-1 and PACS-2, two adaptor proteins that recognize an acidic cluster in the carboxy-terminal domain of polycystin-2. Binding to these adaptor proteins is regulated by the phosphorylation of polycystin-2 by the protein kinase casein kinase 2, required for the routing of polycystin-2 between ER, Golgi and plasma membrane compartments. Our paradigm that polycystin-2 is sorted to and active at both ER and plasma membrane reconciles the previously incongruent views of its localization and function. Furthermore, PACS proteins may represent a novel molecular mechanism for ion channel trafficking, directing acidic cluster-containing ion channels to distinct subcellular compartments.
Köttgen
Michael
M
Renal Division, University Hospital of Freiburg, Freiburg, Germany.
Benzing
Thomas
T
Simmen
Thomas
T
Tauber
Robert
R
Buchholz
Björn
B
Feliciangeli
Sylvain
S
Huber
Tobias B
TB
Schermer
Bernhard
B
Kramer-Zucker
Albrecht
A
Höpker
Katja
K
Simmen
Katia Carmine
KC
Tschucke
Christoph Carl
CC
Sandford
Richard
R
Kim
Emily
E
Thomas
Gary
G
Walz
Gerd
G
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D016415:Sequence Alignment; D050396:TRPP Cation Channels; D033921:Vesicular Transport Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D050396:TRPP Cation Channels; D033921:Vesicular Transport Proteins; C491914:PACS1 protein, human; C499638:PACS2 protein, human