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Modulation of Cl− signaling and ion transport by recruitment of kinases and phosphatases mediated by the regulatory protein IRBIT

Vachel, Laura,Shcheynikov, Nikolay,Yamazaki, Osamu,Fremder, Moran,Ohana, Ehud,Son, Aran,Shin, Dong Min,Yamazaki-Nakazawa, Ai,Yang, Chin-Rang,Knepper, Mark A.,Muallem, Shmuel AAAS 2018 Science signaling Vol.11 No.554
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Combinations to regulate Cl− signalingThe secretion of HCO3−-containing fluids is vital to the function of all epithelia and is enabled in part by the activity of the Na+-coupled HCO3− transporter NBCe1-B. Vachel et al. identified five serine residues in NBCe1-B whose phosphorylation status was controlled by the regulatory protein IRBIT. The phosphorylation status of Ser12 and Ser65 affected the Cl− sensitivity of two intracellular Cl−-sensing motifs. Moreover, IRBIT recruited a distinct kinase/phosphatase pair for each serine residue. The three remaining phosphorylation sites were phosphorylated in distinct combinations that determined the relative basal activity level of NBCe1-B and the potential for further activation by IRBIT. These results demonstrate how distinct phosphorylation patterns may enable epithelial cells to fine-tune the HCO3− transport activity of NBCe1-B in response to varying conditions in different parts of the organ.IRBIT is a multifunctional protein that controls the activity of various epithelial ion transporters including NBCe1-B. Interaction with IRBIT increases NBCe1-B activity and exposes two cryptic Cl−-sensing GXXXP sites that enable regulation of NBCe1-B by intracellular Cl− (Cl−in). Here, phosphoproteomic analysis revealed that IRBIT controlled five phosphorylation sites in NBCe1-B that determined both the active conformation of the transporter and its regulation by Cl−in. Mutational analysis suggested that the phosphorylation status of Ser232, Ser233, and Ser235 was regulated by IRBIT and determined whether NBCe1 transporters are in active or inactive conformations. The absence of phosphorylation at Ser232, Ser233, or Ser235 produced NBCe1-B in the conformations pSer233/pSer235, pSer232/pSer235, or pSer232/pSer233, respectively. The activity of the pSer233/pSer235 form was similar to that of IRBIT-activated NBCe1-B, but it was insensitive to inhibition by Cl−in. The properties of the pSer232/pSer235 form were similar to those of wild-type NBCe1-B, whereas the pSer232/pSer233 form was partially active, further activated by IRBIT, but retained inhibition by Cl−in. Furthermore, IRBIT recruited the phosphatase PP1 and the kinase SPAK to control phosphorylation of Ser65, which affected Cl−in sensing by the 32GXXXP36 motif. IRBIT also recruited the phosphatase calcineurin and the kinase CaMKII to control phosphorylation of Ser12, which affected Cl−in sensing by the 194GXXXP198 motif. Ser232, Ser233, and Ser235 are conserved in all NBCe1 variants and affect their activity. These findings reveal how multiple kinase and phosphatase pathways use phosphorylation sites to fine-tune a transporter, which have important implications for epithelial fluid and HCO3− secretion.

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