Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation

Abstract

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

Cell biology of polycystin-2

“…Binding of PACS2 to PKD2 prevented its movement to the plasma membrane. Conversion of S812 to A within the acidic cluster in human PKD2 resulted in increased expression in the plasma membrane in cultured kidney epithelial cells [38]. Support for this model was obtained by the heterologous expression of wild type and S812A mutant form of PKD2 in Xenopus oocytes [38].…”

“…Conversion of S812 to A within the acidic cluster in human PKD2 resulted in increased expression in the plasma membrane in cultured kidney epithelial cells [38]. Support for this model was obtained by the heterologous expression of wild type and S812A mutant form of PKD2 in Xenopus oocytes [38]. Injection of wild type PKD2 cRNA had no significant effect on channel activity, whereas injection of the S812A mutant resulted in large Na + currents mediated by PKD2.…”

“…It is now accepted that PKD2 can function at the plasma membrane, but its activity there is under complex regulation involving shuttling between ER and plasma membrane, protein-protein interactions, and modes of activation. Specifically, it has been shown that the amount of PKD2 in the plasma membrane is dynamically regulated by interacting proteins (PKD1 [29,35], Polycystin-2 interactor, Golgi-and ER-associated protein-14 (PIGEA-14) [37]), posttranslational modifications (serine phosphorylation by casein kinase 2 (CK2) [38] and glycogen synthase kinase 3 (GSK3) [39]), interaction with other channel subunits in the plasma membrane (PKD1 [29,35,[40][41][42], TRPC1 [11], TRPV4 [43]) (Fig. 2), and finally, activation secondary to cell surface receptor activation (epidermal growth factor receptor (EGFR) [36]).…”

“…Regulated trafficking between ER and plasma membrane-Köttgen et al [38] reasoned that the ER and plasma membrane pools of PKD2 must be dynamically regulated so that PKD2 activity can be tightly controlled (Fig. 2).…”

PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage

“…PACS-2 was initially identified by its role in mediating secretory pathway traffic and formation of contacts between the ER and mitochondria to regulate interorganellar communication and autophagy. [20][21][22][23][24][25][26][27] In response to the death ligand TRAIL (TNF-related apoptosis-inducing ligand), PACS-2 becomes dephosphorylated at Ser 437 , switching PACS-2 to a proapoptotic effector that drives permeabilization of mitochondria and lysosomes, which promotes activation of executioner caspases. 20 Recent studies show that PACS-2 responds to DNA damage by promoting cell cycle arrest and cell survival.…”