Affinage

Showing AHCYL1 — IRBIT is a alias.

AHCYL1

S-adenosylhomocysteine hydrolase-like protein 1 · UniProt O43865

Length
530 aa
Mass
59.0 kDa
Annotated
2026-06-09
54 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AHCYL1/IRBIT is a phosphorylation-gated scaffold and pseudoligand that couples IP3 receptor (IP3R) Ca2+ signaling to the activation of epithelial ion transporters (PMID:12525476, PMID:16793548, PMID:23542070). In resting cells it is sequestered on the IP3R, where multisite serine phosphorylation in its N-terminal PEST region lets it occupy the IP3-binding core and competitively suppress IP3 binding and Ca2+ release, acting as an endogenous pseudoligand (PMID:16793548, PMID:16527252, PMID:42032162). Phosphorylation of IRBIT is set by a PP1 docking site and an ordered serine cascade, with PKA and CK2 phosphorylating distinct N-terminal serines that license IP3R binding (PMID:17635105, PMID:42032162). cAMP/PKA phosphorylation of the IP3R lowers its affinity for IRBIT, so IP3 releases IRBIT to translocate to the plasma membrane and activate bicarbonate/chloride transporters—pNBC1/NBCe1-B, CFTR, Slc26a6, and DRA/SLC26A3—thereby integrating Ca2+ and cAMP signals to drive fluid and HCO3- secretion (PMID:19033647, PMID:23542070, PMID:25237103, PMID:40569378). Mechanistically, IRBIT activates NBCe1-B by competitively relieving its autoinhibitory domain and by recruiting opposing kinases and phosphatases (SPAK and CaMKII versus PP1 and calcineurin) to control a defined set of transporter phosphosites that also tune intracellular Cl- sensing (PMID:21317537, PMID:22012331, PMID:30377224, PMID:33237573); it activates NHE3 through Ca2+/CaMKII-dependent surface trafficking within a NHERF1 macrocomplex (PMID:18829453, PMID:20584908, PMID:27279487). Beyond transport, IRBIT moonlights in nucleotide metabolism by forming a dATP-dependent complex with ribonucleotide reductase to inhibit it and balance dNTP pools and cell-cycle progression (PMID:25237103), suppresses CaMKIIα by blocking calmodulin binding to control tyrosine hydroxylase phosphorylation and catecholamine homeostasis (PMID:25922519), senses S-adenosylhomocysteine to inhibit PIK3C3 and autophagy (PMID:33993848), and promotes apoptosis through Bcl2l10 inhibition and ER–mitochondria Ca2+ transfer at mitochondria-associated membranes (PMID:27995898). Its activities are further shaped by NAD redox state acting as a cofactor and by homo/heteromultimerization with the Long-IRBIT paralog, which can confer opposing regulatory outcomes such as lysosomal versus stabilized AE2 (PMID:33727633, PMID:39985648, PMID:28348216).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2003 High

    Established IRBIT as a physical partner of the IP3R whose binding is governed jointly by IP3 occupancy and phosphorylation, defining it as a regulated IP3R-associated protein.

    Evidence Affinity purification from rat brain microsomes with IP3 elution, in vitro binding and co-IP

    PMID:12525476

    Open questions at the time
    • Functional consequence of the interaction not yet defined
    • Identity of the kinases setting the phospho-dependence unknown
  2. 2006 High

    Defined the inhibitory mechanism: IRBIT is a phosphorylation-dependent pseudoligand that competes with IP3 at the same recognition residues to suppress Ca2+ release.

    Evidence [3H]IP3 competition, in vitro Ca2+ release, live-cell Ca2+ imaging, mutagenesis; direct binding mapping to suppressor and IP3-binding core domains

    PMID:16527252 PMID:16793548

    Open questions at the time
    • Which serines and kinases drive the competent phospho-state not yet resolved
    • Stoichiometry of IRBIT:IP3R unknown
  3. 2006 High

    Showed IRBIT is not solely an IP3R inhibitor but also a required activator of an epithelial transporter, revealing a translocation-based dual function.

    Evidence Co-IP and two-electrode voltage-clamp in Xenopus oocytes showing pNBC1 requires IRBIT for activity

    PMID:16769890

    Open questions at the time
    • Mechanism of transporter activation not yet defined
    • Trigger linking IP3R release to transporter binding unknown
  4. 2007 High

    Mapped the phospho-regulatory logic: a PP1 docking site and an ordered Ser68→Ser71/Ser74 cascade set IRBIT affinity for the IP3R.

    Evidence In vitro PP1 binding, co-IP, phosphosite mutagenesis, [3H]IP3 binding assay

    PMID:17635105

    Open questions at the time
    • Upstream kinases for each serine not identified here
    • How dephosphorylation is triggered physiologically unknown
  5. 2008 High

    Extended IRBIT's activator role to NHE3 and to coordinated CFTR/pNBC1 secretion, establishing it as a hub for epithelial fluid and HCO3- transport.

    Evidence Co-IP, NHE3 transport and surface biotinylation, siRNA, single-channel patch clamp and fluid secretion in sealed pancreatic ducts, domain mapping

    PMID:18829453 PMID:19033647

    Open questions at the time
    • Distinct domain requirements across transporters mechanistically unexplained
    • How a single IRBIT pool coordinates basolateral and luminal targets unknown
  6. 2009 High

    Revealed a transcription-independent moonlighting role: phospho-IRBIT binds CPSF/Fip1 and inhibits poly(A) polymerase, linking IRBIT phosphorylation and oxidative stress to mRNA polyadenylation.

    Evidence Co-IP, in vitro Fip1 binding, in vitro PAP activity assay, Fip1 redistribution imaging, tBHQ stress

    PMID:19224921

    Open questions at the time
    • Physiological mRNA targets not identified
    • Relationship to IRBIT's membrane functions unclear
  7. 2011 High

    Defined the activation mechanism for NBCe1-B as relief of an autoinhibitory domain combined with recruited phosphatase action, and placed IRBIT in opposition to the WNK/SPAK kinase pathway.

    Evidence Electrophysiology with NBCe1-B/IRBIT mutants; siRNA epistasis (SPAK/IRBIT double silencing), co-IP and fluid secretion in ducts

    PMID:21317537 PMID:22012331

    Open questions at the time
    • The extra stimulatory component beyond AID masking not fully explained
    • Generalizability of PP1 recruitment to other transporters not yet tested here
  8. 2013 High

    Established the Ca2+/cAMP integration model: PKA phosphorylation of IP3R releases IRBIT for synergistic activation of CFTR and Slc26a6, validated in knockout mice.

    Evidence Irbit-/- and Slc26a6-/- mice, CFTR currents, Slc26a6 pH assay, fluid secretion, IP3R PKA-site mutagenesis; shared positively charged module mapped across NBCe1-B/CFTR R domain/Slc26a6 STAS

    PMID:23431199 PMID:23542070

    Open questions at the time
    • In vivo relevance to human secretory disease not addressed
    • How Thr49/Ser65 phospho-states are dynamically controlled in vivo unknown
  9. 2014 High

    Uncovered a metabolic function: IRBIT inhibits ribonucleotide reductase in a dATP-dependent manner, coupling it to dNTP pool balance and cell-cycle progression.

    Evidence Co-IP of RNR-IRBIT complex, RNR activity assay, IRBIT knockdown in HeLa with dNTP and cell-cycle readouts

    PMID:25237103

    Open questions at the time
    • Structural basis of dATP stabilization not resolved
    • Coordination with IRBIT's signaling roles unknown
  10. 2015 High

    Broadened IRBIT's regulatory reach to CaMKIIα suppression and catecholamine control, and to interactions with lipid-kinase catalytic cores.

    Evidence Co-IP, CaMKIIα kinase assay and IRBIT KO mice with phospho-TH and behavioral phenotypes; co-IP with PIPKIα/PIPKIIα catalytic residues from cerebellum

    PMID:25922519 PMID:26509711

    Open questions at the time
    • PIPK interaction lacks an in vivo functional readout
    • How CaMKII suppression is balanced against CaMKII-dependent transporter activation unclear
  11. 2016 High

    Showed IRBIT operates at ER-mitochondria contacts, where dephosphorylated IRBIT inhibits Bcl2l10 and promotes pro-apoptotic Ca2+ transfer.

    Evidence Co-IP, MAM fractionation, Ca2+ imaging, cell death assays, dephosphorylation experiments; NHERF1-IRBIT-NHE3 macrocomplex assembly via Ser68

    PMID:27279487 PMID:27995898

    Open questions at the time
    • Trigger coupling apoptotic dephosphorylation to MAM localization not defined
    • Stoichiometry within the NHERF1-IRBIT-NHE3 complex unknown
  12. 2017 Medium

    Established that IRBIT family members multimerize and that N-terminal splicing dictates stability and target selectivity, providing a combinatorial code for IRBIT function.

    Evidence Co-IP for multimerization, protein stability and target-binding selectivity assays across family constructs, expression analysis

    PMID:28348216

    Open questions at the time
    • Physiological abundance of specific multimer combinations unknown
    • Single-lab characterization without in vivo validation
  13. 2018 High

    Resolved the full phospho-regulatory circuit by which IRBIT controls NBCe1-B conformation and Cl- sensitivity through recruited kinases and phosphatases at defined sites.

    Evidence Phosphoproteomics, mutagenesis, electrophysiology, co-IP of recruited SPAK/CaMKII/PP1/calcineurin

    PMID:30377224

    Open questions at the time
    • Dynamic switching between recruited enzymes in vivo not directly observed
    • Generalization of the multi-enzyme recruitment model to other transporters untested
  14. 2020 High

    Defined the structural mechanism of NBCe1-B activation as competitive electrostatic displacement of the autoinhibitory domain by IRBIT's bipartite binding arms, and linked IRBIT-RNR control to tissue homeostasis in vivo.

    Evidence Systematic NBCe1-B/IRBIT mutagenesis with voltage-clamp electrophysiology and co-IP; Drosophila midgut genetics with RNR epistasis

    PMID:32179478 PMID:33237573

    Open questions at the time
    • Drosophila finding is Medium-confidence model-organism genetics
    • Direct structural data on the IRBIT-NBCe1-B interface lacking
  15. 2021 High

    Identified two new ligand-sensing and adaptor functions: SAH-sensing inhibition of PIK3C3/autophagy, and paralog-specific control of AE2 stability and activity.

    Evidence Co-IP, PIK3C3 activity and autophagy flux assays with domain dissection and in vivo validation; AE2 activity assays in IRBIT/L-IRBIT KO cells with bafilomycin rescue

    PMID:33727633 PMID:33993848

    Open questions at the time
    • Physiological conditions raising SAH to engage IRBIT not defined
    • Structural basis of opposing IRBIT vs L-IRBIT effects on AE2 unknown
  16. 2022 Medium

    Linked IRBIT to neurodegeneration-relevant biology by showing tau interacts with IRBIT and alters its proximity to the IP3R.

    Evidence Protein microarray, co-IP from brain and cells, proximity ligation assay

    PMID:35218773

    Open questions at the time
    • No functional consequence of the tau-IRBIT interaction measured
    • Disease relevance not established
  17. 2025 Medium

    Connected IRBIT dosage to cardiac and redox physiology and to a cancer growth pathway, expanding its in vivo and disease-associated roles.

    Evidence AAV9 IRBIT overexpression/knockdown in mice with echocardiography and cardiomyocyte Ca2+ imaging; NAD salvage/redox electrophysiology on NBCe1-B; PREX2-AHCYL1 GEF assays, RAC1 activation, and NSCLC xenografts; IRBIT/LIMA1/SLC26A3 co-IP and activity assays

    PMID:39929439 PMID:39985648 PMID:40365293 PMID:40569378

    Open questions at the time
    • Single-lab in vivo models for cardiac and cancer roles
    • Mechanism linking NAD redox cofactor binding to IRBIT activation not structurally defined
    • Whether PREX2/RAC1 role intersects IRBIT's IP3R functions unknown
  18. 2026 High

    Refined the pseudoligand mechanism by mapping the specific CK2 and PKA phosphosites that create the IP3-binding-core docking surface sufficient to inhibit Ca2+ release.

    Evidence In vitro PKA/CK2 kinase assays, IBC pulldown with defined phospho-mutants, computational binding estimation, Ca2+ imaging

    PMID:42032162

    Open questions at the time
    • In vivo kinase regulation of these sites not demonstrated
    • How these sites coordinate with transporter-activation phospho-states unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IRBIT's many parallel functions—IP3R suppression, transporter activation, RNR inhibition, CaMKII/PIK3C3/PREX2 regulation, and apoptosis—are partitioned spatially and temporally within a single cell remains unresolved.
  • No structural model of full-length IRBIT in any complex
  • Quantitative competition between competing binding partners untested
  • Mechanism selecting which function dominates under a given stimulus unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 4 GO:0140313 molecular sequestering activity 3 GO:0140299 molecular sensor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 3 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-382551 Transport of small molecules 6 R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 1 R-HSA-5357801 Programmed Cell Death 1 R-HSA-8953854 Metabolism of RNA 1 R-HSA-9612973 Autophagy 1
Partners
CAMK2ACFTRITPR1NBCE1-B/SLC4A4 (PNBC1)NHE3/SLC9A3PIK3C3SLC26A3 (DRA)SLC26A6
Complex memberships
CPSF (Fip1)NHERF1-IRBIT-NHE3 macrocomplexribonucleotide reductase (RNR) complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 IRBIT (AHCYL1) was identified as a novel IP3 receptor type 1 (IP3R1)-binding protein that is released from IP3R1 upon IP3 binding. The N-terminal region of IRBIT (the 104 aa appendage) is essential for interaction with IP3R1, and the IRBIT binding region maps to the IP3-binding core of IP3R1. Alkaline phosphatase treatment abolished the interaction, demonstrating that both IP3 and phosphorylation dually regulate the interaction. Affinity purification from rat brain microsomes using immobilized IP3R1 N-terminal domain, IP3 elution, in vitro binding experiments, co-immunoprecipitation The Journal of biological chemistry High 12525476
2006 IRBIT suppresses IP3R activation by competing with IP3 for the same binding site on IP3R. Multiserine phosphorylation of IRBIT is essential for binding; 10 of 12 key IP3R residues for IP3 recognition also participate in IRBIT binding. IRBIT acts as an endogenous 'pseudoligand' of IP3R whose inhibitory activity is modulated by its phosphorylation status. [3H]IP3 binding competition assay, in vitro Ca2+ release assay, Ca2+ imaging in intact cells, mutagenesis Molecular cell High 16793548
2006 IRBIT directly binds to the IP3 receptor (both the suppressor domain and the IP3-binding core are required for strong interaction). A PEST motif, a PDZ-ligand, and Asp-73 on IRBIT are critical for this interaction. IRBIT inhibits both IP3 binding and IP3-induced Ca2+ release from IP3R. Direct in vitro binding assays, mutagenesis, [3H]IP3 binding inhibition, Ca2+ release assay Biochemical and biophysical research communications High 16527252
2006 IRBIT specifically binds to the pancreas-type splicing variant of NBC1 (pNBC1) but not to kidney-type NBC1 (kNBC1). IRBIT binds the N-terminal pNBC1-specific domain, and binding depends on phosphorylation of multiple serine residues in IRBIT. Electrophysiological analysis in Xenopus oocytes showed that pNBC1 requires IRBIT coexpression to manifest substantial transport activity. Co-immunoprecipitation, two-electrode voltage-clamp in Xenopus oocytes, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 16769890
2007 Protein phosphatase-1 (PP1) binds to a conserved docking site on IRBIT preceding the PEST domain and mediates dephosphorylation of IRBIT Ser68. Phosphorylation of Ser68 is required for subsequent phosphorylation of Ser71 and Ser74, whereas phosphorylation of Ser71 and Ser74 (but not Ser68 alone) is sufficient to enable IRBIT inhibition of IP3 binding to IP3R. Mutational inactivation of the PP1 docking site on IRBIT increased IRBIT affinity for IP3R. In vitro PP1 binding assay, co-immunoprecipitation, site-directed mutagenesis, [3H]IP3 binding assay The Biochemical journal High 17635105
2008 IRBIT binds to the C-terminal domain of NHE3 (Na+/H+ exchanger 3) and activates NHE3 activity in a Ca2+-dependent manner. IRBIT-dependent activation involves exocytic trafficking of NHE3 to the plasma membrane, and this activation is blocked by inhibition of calmodulin or CaM-dependent kinase II. Co-expression of IRBIT reverses NHERF2-dependent inhibition of NHE3. Co-immunoprecipitation, NHE3 activity assay, siRNA knockdown, cell surface biotinylation, pharmacological inhibition of CaM/CaMKII The Journal of biological chemistry High 18829453
2008 IRBIT activates both basolateral pNBC1 and luminal CFTR to coordinate fluid and HCO3- secretion in the murine pancreatic duct. siRNA knockdown of IRBIT markedly inhibited ductal pNBC1 and CFTR activities, and fluid and HCO3- secretion. Activation of pNBC1 required only the IRBIT PEST domain, while activation of CFTR required multiple IRBIT domains, indicating distinct mechanisms. Single-channel measurements showed IRBIT regulated CFTR by reducing channel mean close time. Video microscopy of sealed intralobular pancreatic ducts, ion-selective microelectrodes, siRNA knockdown, single-channel patch clamp, domain deletion constructs in HEK cells The Journal of clinical investigation High 19033647
2009 IRBIT associates with the cleavage and polyadenylation specificity factor (CPSF) complex in a phosphorylation-dependent manner. The main IRBIT target within CPSF is the Fip1 subunit. Phosphorylation of the serine-rich region of IRBIT is required for association with Fip1 in vitro and for redistribution of Fip1 to the cytoplasm. IRBIT also interacts with poly(A) polymerase (PAP) and inhibits PAP activity in a phosphorylation-dependent manner. Oxidative stress (tBHQ) increases IRBIT phosphorylation, enhances IRBIT-CPSF interaction, and promotes cytoplasmic distribution of Fip1. Co-immunoprecipitation, in vitro binding with Fip1, in vitro PAP activity assay, RNA recruitment assay, immunofluorescence, phosphorylation analysis The Journal of biological chemistry High 19224921
2010 IRBIT mediates activation of NHE3 by angiotensin II (ANG II) via a CaMKII-dependent pathway. ANG II transiently increases IRBIT-NHE3 binding, which precedes increased NHE3 surface expression and activity. Inhibition of CaMKII blocks ANG II-induced IRBIT-NHE3 binding and NHE3 surface abundance. Mutations of IRBIT Ser-68, Ser-71, and Ser-74 decreased IRBIT binding to NHE3 and reduced ANG II-stimulated NHE3 activity. Co-immunoprecipitation, NHE3 activity assay (fluorometric intracellular pH), cell surface biotinylation, CaMKII pharmacological inhibition, siRNA knockdown, site-directed mutagenesis The Journal of biological chemistry High 20584908
2011 IRBIT opposes the WNK/SPAK kinase pathway by recruiting PP1 to the CFTR/NBCe1-B complex to dephosphorylate these transporters and restore their cell surface expression. WNK kinases act as scaffolds recruiting SPAK, which phosphorylates CFTR and NBCe1-B to reduce their surface expression. IRBIT opposes this effect and also directly stimulates transporter activity. Silencing of both SPAK and IRBIT in the same ducts rescued ductal secretion caused by IRBIT silencing alone (epistasis). siRNA knockdown, genetic epistasis (double silencing), cell surface expression assay, fluid secretion measurement in sealed pancreatic ducts, co-immunoprecipitation, phosphorylation analysis The Journal of clinical investigation High 21317537
2011 IRBIT relieves the autoinhibitory domain (AID) of NBCe1-B to activate it, but the stimulatory effect of IRBIT cannot be explained solely by masking autoinhibitory determinants. A mutant IRBIT resistant to protein phosphatase-1 action stimulates NBCe1-B to an extent 50% greater than removal of the AID alone. An NBCe1-B construct lacking residues 2-16 is fully autoinhibited but cannot be stimulated by IRBIT, indicating that autoinhibitory and IRBIT-binding determinants are not identical. Two-electrode voltage-clamp on Xenopus oocytes, IRBIT and NBCe1-B deletion/mutation constructs American journal of physiology. Cell physiology High 22012331
2013 IRBIT mediates synergistic activation of CFTR and Slc26a6 by Ca2+ and cAMP signaling pathways. In resting cells, IRBIT is sequestered by IP3Rs in the ER. cAMP-dependent phosphorylation of IP3Rs reduces their affinity for IRBIT, enabling IP3-induced dissociation and translocation of IRBIT to CFTR and Slc26a6 at the plasma membrane. This synergistic mechanism was absent in Irbit-/- mice and in mice with IP3Rs bearing mutations preventing PKA phosphorylation. Knockout mice (Irbit-/- and Slc26a6-/-), co-immunoprecipitation, CFTR Cl- current measurement, intracellular pH assay (Slc26a6 activity), fluid secretion measurement, site-directed mutagenesis of IP3R PKA sites Gastroenterology High 23542070
2013 A positively charged module within NBCe1-B (residues 37-65) is required for interaction with and activation by IRBIT and for regulation by PIP2. Phosphorylation of Thr49 is required for regulation by both IRBIT and SPAK. A homologous sequence exists in the CFTR R domain and Slc26a6 STAS domain, both of which bind IRBIT; the R domain is required for CFTR activation by IRBIT. Co-immunoprecipitation, mutagenesis, electrophysiology in Xenopus oocytes, domain deletion analysis Proceedings of the National Academy of Sciences of the United States of America High 23431199
2014 IRBIT forms a dATP-dependent complex with ribonucleotide reductase (RNR), stabilizes dATP in the activity site of RNR, and thereby inhibits RNR enzymatic activity. Formation of the RNR-IRBIT complex is regulated by IRBIT phosphorylation. Ablation of IRBIT in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression. Co-immunoprecipitation of RNR-IRBIT complex, RNR enzymatic activity assay, IRBIT knockdown in HeLa cells with dNTP pool measurement, cell cycle analysis Science (New York, N.Y.) High 25237103
2015 IRBIT binds to CaMKIIα and suppresses its kinase activity by inhibiting the binding of calmodulin to CaMKIIα. In IRBIT-deficient mice, phosphorylation of tyrosine hydroxylase (TH) by CaMKIIα is significantly increased in the ventral tegmental area, leading to elevated catecholamine levels and behavioral abnormalities. Co-immunoprecipitation, CaMKIIα kinase activity assay, IRBIT knockout mice, TH phosphorylation analysis by immunoblot, behavioral assays Proceedings of the National Academy of Sciences of the United States of America High 25922519
2015 IRBIT forms signaling complexes with phosphatidylinositol phosphate kinases (PIPKs), specifically interacting with PIPKIα and PIPKIIα in mouse cerebellum. Two conserved catalytic aspartate residues of PIPKIα and PIPKIIα are required for interaction with IRBIT. Phosphatidylinositol 4-phosphate, Mg2+, and/or ATP interfere with the interaction, indicating IRBIT interacts with the catalytic core. Mutations in the serine-rich region of IRBIT affect selectivity for PIPKIα vs PIPKIIα. IRBIT and PIPKIα interact with NBCe1-B. Co-immunoprecipitation from mouse cerebellum, heterologous expression binding assays, site-directed mutagenesis, immunocytochemistry, in vitro binding PloS one Medium 26509711
2016 IRBIT interacts with the Bcl-2 homolog Bcl2l10 and together they exert additive inhibition of IP3R. Both proteins associate in mitochondria-associated membranes (MAMs). Upon apoptotic stress, IRBIT is dephosphorylated and becomes an inhibitor of Bcl2l10. IRBIT promotes ER-mitochondria contact. By inhibiting Bcl2l10 and promoting ER-mitochondria contact, IRBIT facilitates Ca2+ transfer to mitochondria and promotes apoptosis. Co-immunoprecipitation, subcellular fractionation (MAM isolation), Ca2+ imaging, cell death assays, dephosphorylation experiments, IP3R activity assay eLife High 27995898
2016 NHERF1, NHE3, and IRBIT form a macrocomplex. ANG II induces a concomitant increase in NHERF1 interactions with NHE3 and IRBIT requiring the NHERF1 PDZ1 domain. IRBIT is indispensable for ANG II-provoked increase in NHERF1-NHE3 interactions, and phosphorylation of IRBIT at Ser68 is necessary for assembly of the NHERF1-IRBIT-NHE3 complex and NHE3 activation. Co-immunoprecipitation, dominant negative PDZ1 overexpression, siRNA knockdown of IRBIT, cell surface biotinylation, fluorescence imaging American journal of physiology. Renal physiology Medium 27279487
2017 IRBIT family proteins form homo- and heteromultimers. N-terminal splicing of Long-IRBIT changes protein stability and selectivity for target molecules. Different IRBIT family members exhibit distinct mRNA expression patterns and different target selectivities determined by N-terminal diversity and multimer combinations. Co-immunoprecipitation, protein stability assays, target binding assays with multiple IRBIT family constructs, RT-PCR expression analysis Proceedings of the National Academy of Sciences of the United States of America Medium 28348216
2018 IRBIT controls five phosphorylation sites in NBCe1-B that determine active vs. inactive transporter conformation and regulate sensitivity to intracellular Cl-. IRBIT recruits PP1 and SPAK to control phosphorylation of Ser65 (affecting Cl- sensing via 32GXXXP36 motif), and recruits calcineurin and CaMKII to control phosphorylation of Ser12 (affecting Cl- sensing via 194GXXXP198 motif). Phosphorylation status of Ser232, Ser233, Ser235 determines active/inactive conformations of NBCe1-B. Phosphoproteomic analysis, mutagenesis, electrophysiology, co-immunoprecipitation of recruited kinases/phosphatases Science signaling High 30377224
2020 IRBIT activates NBCe1-B by releasing the autoinhibitory domain (AID, acting as a brake) from the transmembrane domain via competitive binding. The AID (residues 40-85) binds to the transmembrane domain via electrostatic attraction to slow NBCe1-B. IRBIT binding domain spans residues 1-52 with two arms (negatively charged residues 1-24 and positively charged residues 40-52). Negatively charged Asp/Glu residues plus Ser/Thr residues in the IRBIT PEST domain are required for NBCe1-B interaction. Systematic mutagenesis of NBCe1-B and IRBIT, two-electrode voltage-clamp in Xenopus oocytes, co-immunoprecipitation The Journal of physiology High 33237573
2020 IRBIT expression in intestinal stem cell progeny in the Drosophila midgut regulates their differentiation into enterocytes via suppression of RNR activity. Disruption of the IRBIT-RNR regulatory circuit causes premature loss of intestinal tissue integrity, and age-related dysplasia can be reversed by suppression of RNR activity in ISC progeny. Drosophila genetics (IRBIT loss-of-function, RNR inhibition), histology of midgut epithelium, intestinal stem cell differentiation assays iScience Medium 32179478
2021 AHCYL1 (IRBIT) acts as a SAH (S-adenosyl-l-homocysteine) sensor to inhibit autophagy through PIK3C3. The C-terminus of AHCYL1 interacts with SAH specifically, and this SAH binding promotes the N-terminus to bind the catalytic domain of PIK3C3 and inhibit it, independently of MTORC1. Co-immunoprecipitation, PIK3C3 activity assay, autophagy flux assay, AHCYL1 deletion constructs, in vivo validation Autophagy High 33993848
2021 Both IRBIT and Long-IRBIT interact with anion exchanger AE2 through the conserved AHCY-homologous domain of IRBIT/L-IRBIT binding the N-terminal cytoplasmic region of AE2. L-IRBIT KO reduces AE2 activity and protein expression, while IRBIT KO does not. IRBIT binding facilitates lysosomal degradation of AE2, which is inhibited by coexisting L-IRBIT, revealing opposing regulatory roles. Co-immunoprecipitation, AE2 activity assay (intracellular pH), IRBIT/L-IRBIT KO cells, bafilomycin A1 treatment (lysosomal inhibition), cell volume regulation assay, cell migration assay Scientific reports High 33727633
2022 Endogenous tau physically interacts with AHCYL1/IRBIT in brain tissues and cultured cells. Tau overexpression modifies the close localization of AHCYL1/IRBIT to IP3R at the endoplasmic reticulum. Protein microarray binding assay with recombinant tau, co-immunoprecipitation from brain tissue and cultured cells, proximity ligation assay The Journal of biological chemistry Medium 35218773
2025 IRBIT overexpression in mice using AAV9 causes cardiac hypertrophy with impaired systolic function. IRBIT overexpression decreases Ca2+ transient amplitude, slows Ca2+ transient rise, reduces Ca2+ wave propagation velocity, increases the dyssynchrony index, and reduces nuclear envelope invaginations in isolated cardiomyocytes. IP3R mRNA levels are decreased in IRBIT-overexpressing hearts. AAV9-shRNA reduction of IRBIT expression does not alter heart morphometric parameters. AAV9-mediated overexpression and shRNA knockdown in mice, echocardiography, isolated cardiomyocyte Ca2+ imaging, fluorescence microscopy Journal of molecular and cellular cardiology Medium 39929439
2025 AHCYL1 interacts with PREX2 (a Rac1 GEF) and enhances PREX2 GEF activity by alleviating mutual inhibition between PREX2 and PTEN, leading to increased RAC1 activation and NSCLC cell growth. Pull-down assay with LC-MS/MS identification, co-immunoprecipitation, in vitro GEF activity assay, active RAC1 pull-down assay, PREX2/AHCYL1 knockdown, xenograft mouse model Theranostics Medium 40365293
2025 IRBIT and LIMA1 associate with the Cl-/HCO3- exchanger SLC26A3 (DRA) under basal conditions, and this association increases with cAMP/ATP stimulation. KD of IRBIT or LIMA1 reduces cAMP/Ca2+-stimulated DRA activity without altering basal activity. Maximum ATP (but not maximal forskolin) stimulation of DRA is IRBIT-dependent. cAMP/ATP-induced elevation of intracellular Ca2+ is also IRBIT-dependent. cAMP/ATP stimulation increases coprecipitation of LIMA1 with both IRBIT and DRA. Co-immunoprecipitation, siRNA knockdown, DRA activity assay (intracellular pH), Ca2+ imaging, cell surface biotinylation American journal of physiology. Cell physiology Medium 40569378
2026 Phosphorylation of IRBIT S80, S84, and S85 (by casein kinase 2) provides binding sites for the IP3-binding core (IBC) of IP3R and is sufficient to compete with IP3 for the IP3-binding pocket. S68 is the predominant phosphorylation site but is not required for IP3R binding. PKA phosphorylates S62/S64/S66; CK2 phosphorylates S80/T82/S84/S85. IRBIT-S68A/S80D/S84D/S85D was sufficient to inhibit IP3R-mediated Ca2+ release in living cells. In vitro kinase assay (PKA, CK2), pulldown assay with IBC domain, computational binding estimation, Ca2+ imaging in living cells, site-directed mutagenesis Communications biology High 42032162
2025 NAD modulates NBCe1-B activation by serving as a cofactor of IRBIT or L-IRBIT. Blocking the NAD salvage pathway decreases NBCe1-B activation by the IRBITs. The oxidized form NAD+ enhances, while the reduced form NADH decreases, NBCe1-B activity, linking cellular redox state to IRBIT-dependent pH regulation. Electrophysiology (Xenopus oocyte or mammalian cell NBCe1-B activity assay), NAD salvage pathway inhibition, NAD+/NADH administration, IRBIT constructs Science China. Life sciences Medium 39985648

Source papers

Stage 0 corpus · 54 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 IRBIT, a novel inositol 1,4,5-trisphosphate (IP3) receptor-binding protein, is released from the IP3 receptor upon IP3 binding to the receptor. The Journal of biological chemistry 170 12525476
2006 IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein, specifically binds to and activates pancreas-type Na+/HCO3- cotransporter 1 (pNBC1). Proceedings of the National Academy of Sciences of the United States of America 143 16769890
2006 IRBIT suppresses IP3 receptor activity by competing with IP3 for the common binding site on the IP3 receptor. Molecular cell 141 16793548
2008 IRBIT coordinates epithelial fluid and HCO3- secretion by stimulating the transporters pNBC1 and CFTR in the murine pancreatic duct. The Journal of clinical investigation 111 19033647
2011 IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway. The Journal of clinical investigation 87 21317537
2013 Irbit mediates synergy between ca(2+) and cAMP signaling pathways during epithelial transport in mice. Gastroenterology 80 23542070
2010 Activation of Na+/H+ exchanger NHE3 by angiotensin II is mediated by inositol 1,4,5-triphosphate (IP3) receptor-binding protein released with IP3 (IRBIT) and Ca2+/calmodulin-dependent protein kinase II. The Journal of biological chemistry 70 20584908
2013 Convergence of IRBIT, phosphatidylinositol (4,5) bisphosphate, and WNK/SPAK kinases in regulation of the Na+-HCO3- cotransporters family. Proceedings of the National Academy of Sciences of the United States of America 68 23431199
2008 IRBIT, inositol 1,4,5-triphosphate (IP3) receptor-binding protein released with IP3, binds Na+/H+ exchanger NHE3 and activates NHE3 activity in response to calcium. The Journal of biological chemistry 63 18829453
2016 IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact. eLife 62 27995898
2011 Relief of autoinhibition of the electrogenic Na-HCO(3) [corrected] cotransporter NBCe1-B: role of IRBIT vs.amino-terminal truncation. American journal of physiology. Cell physiology 55 22012331
2007 Protein phosphatase-1 is a novel regulator of the interaction between IRBIT and the inositol 1,4,5-trisphosphate receptor. The Biochemical journal 46 17635105
2014 Enzyme regulation. IRBIT is a novel regulator of ribonucleotide reductase in higher eukaryotes. Science (New York, N.Y.) 45 25237103
2014 IRBIT: a regulator of ion channels and ion transporters. Biochimica et biophysica acta 40 24518248
2015 IRBIT regulates CaMKIIα activity and contributes to catecholamine homeostasis through tyrosine hydroxylase phosphorylation. Proceedings of the National Academy of Sciences of the United States of America 38 25922519
2006 Binding of IRBIT to the IP3 receptor: determinants and functional effects. Biochemical and biophysical research communications 38 16527252
2008 The IRBIT domain adds new functions to the AHCY family. BioEssays : news and reviews in molecular, cellular and developmental biology 36 18536033
2016 Mutations in the IRBIT domain of ITPR1 are a frequent cause of autosomal dominant nonprogressive congenital ataxia. Clinical genetics 31 27062503
2012 The WNK/SPAK and IRBIT/PP1 pathways in epithelial fluid and electrolyte transport. Physiology (Bethesda, Md.) 31 23026752
2009 Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation. The Journal of biological chemistry 31 19224921
2012 AHCYL1 is mediated by estrogen-induced ERK1/2 MAPK cell signaling and microRNA regulation to effect functional aspects of the avian oviduct. PloS one 29 23145124
2021 AHCYL1 senses SAH to inhibit autophagy through interaction with PIK3C3 in an MTORC1-independent manner. Autophagy 28 33993848
2006 Suppression and overexpression of adenosylhomocysteine hydrolase-like protein 1 (AHCYL1) influences zebrafish embryo development: a possible role for AHCYL1 in inositol phospholipid signaling. The Journal of biological chemistry 27 16754674
2012 ROCK-phosphorylated vimentin modifies mutant huntingtin aggregation via sequestration of IRBIT. Molecular neurodegeneration 24 22929228
2010 IRBIT: it is everywhere. Neurochemical research 22 21152975
2009 An IRBIT homologue lacks binding activity to inositol 1,4,5-trisphosphate receptor due to the unique N-terminal appendage. Journal of neurochemistry 22 19220705
2016 The NHERF1 PDZ1 domain and IRBIT interact and mediate the activation of Na+/H+ exchanger 3 by ANG II. American journal of physiology. Renal physiology 21 27279487
2012 Paradoxical expression of AHCYL1 affecting ovarian carcinogenesis between chickens and women. Experimental biology and medicine (Maywood, N.J.) 21 22826361
2018 Modulation of Cl- signaling and ion transport by recruitment of kinases and phosphatases mediated by the regulatory protein IRBIT. Science signaling 18 30377224
2017 Splicing variation of Long-IRBIT determines the target selectivity of IRBIT family proteins. Proceedings of the National Academy of Sciences of the United States of America 16 28348216
2020 Protective Role of IRBIT on Sodium Bicarbonate Cotransporter-n1 for Migratory Cancer Cells. Pharmaceutics 15 32867284
2014 AHCYL2 (long-IRBIT) as a potential regulator of the electrogenic Na(+)-HCO3(-) cotransporter NBCe1-B. FEBS letters 15 24472682
2022 RyR2/IRBIT regulates insulin gene transcript, insulin content, and secretion in the insulinoma cell line INS-1. Scientific reports 13 35562179
2020 IRBIT activates NBCe1-B by releasing the auto-inhibition module from the transmembrane domain. The Journal of physiology 13 33237573
2012 IRBIT reduces the apparent affinity for intracellular Mg²⁺ in inhibition of the electrogenic Na⁺-HCO₃⁻ cotransporter NBCe1-B. Biochemical and biophysical research communications 13 22771795
2020 IRBIT Directs Differentiation of Intestinal Stem Cell Progeny to Maintain Tissue Homeostasis. iScience 11 32179478
2022 Unbiased proteomic profiling reveals the IP3R modulator AHCYL1/IRBIT as a novel interactor of microtubule-associated protein tau. The Journal of biological chemistry 10 35218773
2015 IRBIT Interacts with the Catalytic Core of Phosphatidylinositol Phosphate Kinase Type Iα and IIα through Conserved Catalytic Aspartate Residues. PloS one 10 26509711
2020 Multiple acid-base and electrolyte disturbances upregulate NBCn1, NBCn2, IRBIT and L-IRBIT in the mTAL. The Journal of physiology 8 32359081
2013 IRBIT plays an important role in NHE3-mediated pHi regulation in HSG cells. Biochemical and biophysical research communications 8 23769829
2024 NRAS Mutant Dictates AHCYL1-Governed ER Calcium Homeostasis for Melanoma Tumor Growth. Molecular cancer research : MCR 7 38294692
2021 Both IRBIT and long-IRBIT bind to and coordinately regulate Cl-/HCO3- exchanger AE2 activity through modulating the lysosomal degradation of AE2. Scientific reports 7 33727633
2019 MAP‑1B, PACS‑2 and AHCYL1 are regulated by miR‑34A/B/C and miR‑449 in neuroplasticity following traumatic spinal cord injury in rats: Preliminary explorative results from microarray data. Molecular medicine reports 7 31432119
2022 Synaptic plasticity in hippocampal CA1 neurons of mice lacking inositol-1,4,5-trisphosphate receptor-binding protein released with IP3 (IRBIT). Learning & memory (Cold Spring Harbor, N.Y.) 6 35351819
2019 Low IRBIT Levels Are Associated With Chemo-resistance in Gastric Cancer Patients. Anticancer research 6 31366495
2023 S-adenosylhomocysteine hydrolase-like protein 1 (AHCYL1) inhibits lung cancer tumorigenesis by regulating cell plasticity. Biology direct 5 36872327
2012 The discovery and structural investigation of the IP₃ receptor and the associated IRBIT protein. Advances in experimental medicine and biology 5 22453947
2025 Cardiac hypertrophy induced by overexpression of IP3-released inositol 1, 4, 5-trisphosphate receptor-binding protein (IRBIT). Journal of molecular and cellular cardiology 4 39929439
2023 Dietary sodium enhances the expression of SLC4 family transporters, IRBIT, L-IRBIT, and PP1 in rat kidney: Insights into the molecular mechanism for renal sodium handling. Frontiers in physiology 4 37082243
2025 Redox state of NAD modulates the activation of Na-bicarbonate cotransporter NBCe1-B via IRBIT and L-IRBIT. Science China. Life sciences 3 39985648
2022 Genetic variants in SCNN1B and AHCYL1 are associated with eggshell quality in Chinese domestic laying ducks (Anas platyrhynchos). British poultry science 2 34923880
2025 AHCYL1 mediates the tumor-promoting effect of PREX2 in non-small cell lung carcinoma. Theranostics 1 40365293
2026 Deciphering the multi-site phos-code of IRBIT underlying its binding to IP3R. Communications biology 0 42032162
2025 IRBIT and LIMA1 associate with and are necessary for epithelial cell SLC26A3 (DRA) stimulation by cAMP/ATP. American journal of physiology. Cell physiology 0 40569378

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