title: Regulation of SLC26A3 activity by NHERF4 PDZ-mediated interaction.
abstract: SLC26A3 functions as a chloride/bicarbonate anion exchanger expressed in the secretory epithelial cells in the intestine, pancreas, and salivary glands. SLC26A3 has a C-terminal class I PDZ binding motif that assembles regulatory factors or other transporters by anchoring to various PDZ scaffold proteins. NHERF4 is an epithelial-enriched PDZ domain scaffold protein that has attracted attention because of its enriched tissue expression in the intestine and kidney. In this study, we identified SLC26A3 as a novel binding transporter of NHERF4. We investigated the functional role of NHERF4 in the regulation of SLC26A3 by using integrated biochemical and physiological approaches. A direct protein-protein interaction was identified between the PDZ-binding motif of SLC26A3 and the third PDZ domain of NHERF4. Interaction with NHERF4 decreased the level of SLC26A3 expression on the plasma membrane, which led to reduced SLC26A3 anion exchange activity. Notably, interaction with NHERF4 induced rapid internalisation of SLC26A3 from the plasma membrane. The SLC26A3-NHERF4 interaction was modulated by phosphorylation; serine 329 of NHERF4-PDZ3 played a critical role in modulating binding selectivity. Our findings suggest that NHERF4 is a novel modulator of luminal fluidity in the intestine by adjusting SLC26A3 expression and activity through a phosphorylation-dependent mechanism.
authors.affiliation: Department of Pharmacology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Nam
authors.forename: Joonhee
authors.initials: J
authors.lastname: Park
authors.forename: Dong-Won
authors.initials: DW
authors.lastname: Kang
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Jae Seok
authors.initials: JS
authors.lastname: Yoon
mesh_terms: D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism*; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism; D005753:Gastric Mucosa / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D054731:PDZ Domains; D010750:Phosphoproteins / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D000076988:Sulfate Transporters
chemical_list: D027963:Chloride-Bicarbonate Antiporters; D010750:Phosphoproteins; C081011:SLC26A3 protein, human; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters; C093376:sodium-hydrogen exchanger regulatory factor