Convergence of IRBIT, phosphatidylinositol (4,5) bisphosphate, and WNK/SPAK kinases in regulation of the Na+-HCO3 - cotransporters family

Jeong Hee Hong, Dongki Yang, Nikolay Shcheynikov, Ehud Ohana, DongMin Shin, Shmuel Muallem

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Fluid and HCO3 - secretion is a vital function of secretory epithelia, involving basolateral HCO3 - entry through the Na+-HCO3 - cotransporter (NBC) NBCe1-B, and luminal HCO3 - exit mediated by cystic fibrosis transmembrane conductance regulator (CFTR) and solute carrier family 26 (SLC26) Cl-/HCO3 - exchangers. HCO3 - secretion is highly regulated, with the WNK/SPAK kinase pathway setting the resting state and the IRBIT/PP1 pathway setting the stimulated state. However, we know little about the relationships between the WNK/SPAK and IRBIT/PP1 sites in the regulation of the transporters. The first 85 N-terminal amino acids of NBCe1-B function as an autoinhibitory domain. Here we have identified a positively charged module within NBCe1-B(37-65) that is conserved in NBCn1-A and all 20 members of the NBC superfamily except NBCe1-A. This module is required for the interaction and activation of NBCe1-B and NBCn1-A by IRBIT and their regulation by phosphatidylinositol 4,5- bisphosphate (PIP 2). Activation of the transporters by IRBIT and PIP2 is nonadditive but complementary. Phosphorylation of Ser65 mediates regulation of NBCe1-B by SPAK, and phosphorylation of Thr49 is required for regulation by IRBIT and SPAK. Sequence searches using the NBCe1-B regulatory module as a template identified a homologous sequence in the CFTR R domain and Slc26a6 sulfat transporter and antisigma factor antagonist (STAS) domain. Accordingly, the R and STAS domains bind IRBIT, and the R domain is required for activation of CFTR by IRBIT. These findings reveal convergence of regulatory modalities in a conserved domain of the NBC that may be present in other HCO3 - transporters and thus in the regulation of epithelial fluid and HCO3 - secretion.

Original languageEnglish
Pages (from-to)4105-4110
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number10
DOIs
Publication statusPublished - 2013 Mar 5

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Cystic Fibrosis Transmembrane Conductance Regulator
Phosphatidylinositols
Fluids and Secretions
Phosphotransferases
Phosphorylation
Chloride-Bicarbonate Antiporters
Sequence Homology
Epithelium
Amino Acids

All Science Journal Classification (ASJC) codes

  • General

Cite this

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title = "Convergence of IRBIT, phosphatidylinositol (4,5) bisphosphate, and WNK/SPAK kinases in regulation of the Na+-HCO3 - cotransporters family",
abstract = "Fluid and HCO3 - secretion is a vital function of secretory epithelia, involving basolateral HCO3 - entry through the Na+-HCO3 - cotransporter (NBC) NBCe1-B, and luminal HCO3 - exit mediated by cystic fibrosis transmembrane conductance regulator (CFTR) and solute carrier family 26 (SLC26) Cl-/HCO3 - exchangers. HCO3 - secretion is highly regulated, with the WNK/SPAK kinase pathway setting the resting state and the IRBIT/PP1 pathway setting the stimulated state. However, we know little about the relationships between the WNK/SPAK and IRBIT/PP1 sites in the regulation of the transporters. The first 85 N-terminal amino acids of NBCe1-B function as an autoinhibitory domain. Here we have identified a positively charged module within NBCe1-B(37-65) that is conserved in NBCn1-A and all 20 members of the NBC superfamily except NBCe1-A. This module is required for the interaction and activation of NBCe1-B and NBCn1-A by IRBIT and their regulation by phosphatidylinositol 4,5- bisphosphate (PIP 2). Activation of the transporters by IRBIT and PIP2 is nonadditive but complementary. Phosphorylation of Ser65 mediates regulation of NBCe1-B by SPAK, and phosphorylation of Thr49 is required for regulation by IRBIT and SPAK. Sequence searches using the NBCe1-B regulatory module as a template identified a homologous sequence in the CFTR R domain and Slc26a6 sulfat transporter and antisigma factor antagonist (STAS) domain. Accordingly, the R and STAS domains bind IRBIT, and the R domain is required for activation of CFTR by IRBIT. These findings reveal convergence of regulatory modalities in a conserved domain of the NBC that may be present in other HCO3 - transporters and thus in the regulation of epithelial fluid and HCO3 - secretion.",
author = "Hong, {Jeong Hee} and Dongki Yang and Nikolay Shcheynikov and Ehud Ohana and DongMin Shin and Shmuel Muallem",
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Convergence of IRBIT, phosphatidylinositol (4,5) bisphosphate, and WNK/SPAK kinases in regulation of the Na+-HCO3 - cotransporters family. / Hong, Jeong Hee; Yang, Dongki; Shcheynikov, Nikolay; Ohana, Ehud; Shin, DongMin; Muallem, Shmuel.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 10, 05.03.2013, p. 4105-4110.

Research output: Contribution to journalArticle

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T1 - Convergence of IRBIT, phosphatidylinositol (4,5) bisphosphate, and WNK/SPAK kinases in regulation of the Na+-HCO3 - cotransporters family

AU - Hong, Jeong Hee

AU - Yang, Dongki

AU - Shcheynikov, Nikolay

AU - Ohana, Ehud

AU - Shin, DongMin

AU - Muallem, Shmuel

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N2 - Fluid and HCO3 - secretion is a vital function of secretory epithelia, involving basolateral HCO3 - entry through the Na+-HCO3 - cotransporter (NBC) NBCe1-B, and luminal HCO3 - exit mediated by cystic fibrosis transmembrane conductance regulator (CFTR) and solute carrier family 26 (SLC26) Cl-/HCO3 - exchangers. HCO3 - secretion is highly regulated, with the WNK/SPAK kinase pathway setting the resting state and the IRBIT/PP1 pathway setting the stimulated state. However, we know little about the relationships between the WNK/SPAK and IRBIT/PP1 sites in the regulation of the transporters. The first 85 N-terminal amino acids of NBCe1-B function as an autoinhibitory domain. Here we have identified a positively charged module within NBCe1-B(37-65) that is conserved in NBCn1-A and all 20 members of the NBC superfamily except NBCe1-A. This module is required for the interaction and activation of NBCe1-B and NBCn1-A by IRBIT and their regulation by phosphatidylinositol 4,5- bisphosphate (PIP 2). Activation of the transporters by IRBIT and PIP2 is nonadditive but complementary. Phosphorylation of Ser65 mediates regulation of NBCe1-B by SPAK, and phosphorylation of Thr49 is required for regulation by IRBIT and SPAK. Sequence searches using the NBCe1-B regulatory module as a template identified a homologous sequence in the CFTR R domain and Slc26a6 sulfat transporter and antisigma factor antagonist (STAS) domain. Accordingly, the R and STAS domains bind IRBIT, and the R domain is required for activation of CFTR by IRBIT. These findings reveal convergence of regulatory modalities in a conserved domain of the NBC that may be present in other HCO3 - transporters and thus in the regulation of epithelial fluid and HCO3 - secretion.

AB - Fluid and HCO3 - secretion is a vital function of secretory epithelia, involving basolateral HCO3 - entry through the Na+-HCO3 - cotransporter (NBC) NBCe1-B, and luminal HCO3 - exit mediated by cystic fibrosis transmembrane conductance regulator (CFTR) and solute carrier family 26 (SLC26) Cl-/HCO3 - exchangers. HCO3 - secretion is highly regulated, with the WNK/SPAK kinase pathway setting the resting state and the IRBIT/PP1 pathway setting the stimulated state. However, we know little about the relationships between the WNK/SPAK and IRBIT/PP1 sites in the regulation of the transporters. The first 85 N-terminal amino acids of NBCe1-B function as an autoinhibitory domain. Here we have identified a positively charged module within NBCe1-B(37-65) that is conserved in NBCn1-A and all 20 members of the NBC superfamily except NBCe1-A. This module is required for the interaction and activation of NBCe1-B and NBCn1-A by IRBIT and their regulation by phosphatidylinositol 4,5- bisphosphate (PIP 2). Activation of the transporters by IRBIT and PIP2 is nonadditive but complementary. Phosphorylation of Ser65 mediates regulation of NBCe1-B by SPAK, and phosphorylation of Thr49 is required for regulation by IRBIT and SPAK. Sequence searches using the NBCe1-B regulatory module as a template identified a homologous sequence in the CFTR R domain and Slc26a6 sulfat transporter and antisigma factor antagonist (STAS) domain. Accordingly, the R and STAS domains bind IRBIT, and the R domain is required for activation of CFTR by IRBIT. These findings reveal convergence of regulatory modalities in a conserved domain of the NBC that may be present in other HCO3 - transporters and thus in the regulation of epithelial fluid and HCO3 - secretion.

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