Affinage

AHCYL1

S-adenosylhomocysteine hydrolase-like protein 1 · UniProt O43865

Length
530 aa
Mass
59.0 kDa
Annotated
2026-04-28
54 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AHCYL1 (IRBIT) is a phosphorylation-regulated multifunctional scaffold that integrates calcium signaling, ion transport, nucleotide metabolism, mRNA processing, and autophagy. When phosphorylated at S80/S84/S85 by CK2, IRBIT acts as a pseudoligand that competitively occupies the IP3-binding core of IP3 receptors, suppressing IP3-induced Ca2+ release; IP3 binding or PP1-mediated dephosphorylation releases IRBIT from IP3Rs, enabling it to translocate and activate a broad array of epithelial ion transporters—including NBCe1-B, CFTR, NHE3, Slc26a6, NBCn1, and DRA—by displacing their autoinhibitory domains and recruiting kinase/phosphatase complexes (PP1, SPAK, CaMKII, calcineurin) that control transporter phosphorylation and surface expression (PMID:16793548, PMID:22012331, PMID:21317537, PMID:30377224, PMID:40569378). Beyond ion transport, IRBIT inhibits ribonucleotide reductase in a dATP- and phosphorylation-dependent manner to regulate dNTP pools and cell cycle progression, suppresses poly(A) polymerase activity through interaction with CPSF/Fip1 to regulate mRNA polyadenylation, inhibits CaMKIIα to control catecholamine homeostasis, senses S-adenosyl-L-homocysteine to inhibit PIK3C3-dependent autophagy, and modulates apoptosis by interacting with Bcl2l10 at mitochondria-associated membranes to promote ER-to-mitochondria Ca2+ transfer (PMID:25237103, PMID:19224921, PMID:25922519, PMID:33993848, PMID:27995898).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    The discovery of IRBIT as an IP3R1-binding protein whose interaction requires phosphorylation established AHCYL1 as a regulated component of IP3 receptor signaling, answering how IP3R activity might be modulated by endogenous protein ligands.

    Evidence Affinity purification, co-immunoprecipitation, and alkaline phosphatase treatment in vitro

    PMID:12525476

    Open questions at the time
    • Specific phosphorylation sites not yet mapped
    • Functional consequence of IRBIT binding on IP3R channel activity not demonstrated
    • Identity of kinase(s) unknown
  2. 2006 High

    Establishing that IRBIT competes with IP3 for 10 of 12 shared binding residues on IP3R, and that multiserine phosphorylation of IRBIT is essential, defined IRBIT as a bona fide pseudoligand/competitive inhibitor of IP3R and simultaneously revealed its first non-IP3R target, the pancreatic sodium bicarbonate cotransporter pNBC1.

    Evidence [3H]IP3 binding competition, Ca2+ imaging, mutagenesis for IP3R interaction; co-IP and two-electrode voltage clamp in Xenopus oocytes for pNBC1 activation

    PMID:16527252 PMID:16769890 PMID:16793548

    Open questions at the time
    • Mechanism by which IRBIT activates pNBC1 unknown
    • In vivo significance of dual IP3R/pNBC1 regulation not tested
    • Phosphorylation site hierarchy unresolved
  3. 2007 High

    Identification of PP1 as a direct IRBIT-binding phosphatase that dephosphorylates S68—a gatekeeper for subsequent S71/S74 phosphorylation—established the phosphorylation cascade controlling IRBIT's affinity for IP3R and introduced IRBIT as a PP1 substrate specifier.

    Evidence In vitro phosphatase assays, mass spectrometry, site-directed mutagenesis, co-immunoprecipitation

    PMID:17635105

    Open questions at the time
    • Kinase responsible for S71/S74 phosphorylation not identified
    • In vivo dynamics of phosphorylation cycle unknown
  4. 2008 High

    Demonstrating that IRBIT coordinates pancreatic duct secretion by simultaneously activating basolateral pNBC1 and luminal CFTR through distinct domains, and separately activates NHE3 via CaMKII-dependent trafficking, established IRBIT as a master regulator of epithelial ion transport.

    Evidence siRNA knockdown, ion-selective microelectrodes, single-channel recordings, domain constructs for CFTR/pNBC1; co-IP and surface biotinylation for NHE3

    PMID:18829453 PMID:19033647

    Open questions at the time
    • Structural basis for distinct domain requirements for CFTR vs. pNBC1 unknown
    • Whether IRBIT-NHE3 regulation operates in vivo not tested
  5. 2009 High

    Discovery that IRBIT binds CPSF/Fip1 and inhibits poly(A) polymerase in a phosphorylation-dependent manner revealed an unexpected role outside ion transport, linking IRBIT to mRNA 3′-end processing and broadening its functional repertoire.

    Evidence Co-immunoprecipitation, RNA pulldown, in vitro PAP activity assay, immunofluorescence

    PMID:19224921

    Open questions at the time
    • Target mRNAs regulated by IRBIT-mediated polyadenylation control not identified
    • Physiological relevance of IRBIT-PAP inhibition in vivo not demonstrated
  6. 2011 High

    Elucidation that IRBIT activates NBCe1-B by releasing an autoinhibitory domain, and that IRBIT antagonizes WNK/SPAK kinase signaling by recruiting PP1 to dephosphorylate CFTR and NBCe1-B for surface expression, established the molecular mechanism by which IRBIT orchestrates epithelial secretion through phosphatase/kinase balance.

    Evidence Two-electrode voltage clamp with deletion mutagenesis; siRNA epistasis, phosphoprotein analysis, co-IP for SPAK/PP1 pathway

    PMID:21317537 PMID:22012331

    Open questions at the time
    • Structural details of IRBIT-AID interaction unknown
    • Whether IRBIT-PP1 axis operates in all IRBIT-regulated transporters untested
  7. 2013 High

    Identification of a conserved positively charged regulatory module shared across NBCe1-B, NBCn1-A, CFTR, and Slc26a6 as the common IRBIT-binding motif, together with in vivo demonstration that IRBIT mediates Ca2+/cAMP synergy in pancreatic secretion using knockout mice, unified the mechanism of IRBIT-dependent transporter activation and validated it physiologically.

    Evidence Systematic mutagenesis and electrophysiology across multiple transporters; Irbit−/− and Slc26a6−/− mouse models with functional secretion assays

    PMID:23431199 PMID:23542070

    Open questions at the time
    • Whether the conserved module is sufficient for IRBIT regulation in all family members not fully tested
    • Tissue-specific phenotypes of Irbit−/− mice beyond pancreas/salivary gland not characterized
  8. 2014 High

    Discovery that IRBIT forms a dATP-dependent complex with ribonucleotide reductase to inhibit RNR activity and control dNTP pools revealed a fundamental role in nucleotide metabolism and cell cycle progression, far beyond calcium signaling.

    Evidence Co-IP, in vitro RNR activity assays, dNTP pool quantification, cell cycle analysis in IRBIT-depleted HeLa cells

    PMID:25237103

    Open questions at the time
    • Structural basis of dATP-dependent IRBIT-RNR complex unknown
    • Whether RNR regulation is conserved across all IRBIT-expressing tissues untested
  9. 2015 High

    Showing that IRBIT suppresses CaMKIIα kinase activity by blocking calmodulin binding, with IRBIT-deficient mice exhibiting elevated catecholamine levels and behavioral abnormalities, established IRBIT as a neuronal signaling modulator controlling dopaminergic function.

    Evidence Co-IP, kinase activity assays, IRBIT-deficient mouse behavioral analysis, TH phosphorylation measurements

    PMID:25922519

    Open questions at the time
    • Whether CaMKIIα inhibition operates in non-neuronal tissues unclear
    • Contribution of CaMKIIα inhibition vs. IP3R regulation to behavioral phenotype not dissected
  10. 2016 High

    Demonstration that IRBIT and Bcl2l10 cooperate at mitochondria-associated membranes to regulate IP3R and that apoptotic stress-induced dephosphorylation converts IRBIT from a Bcl2l10 cooperator to an inhibitor, promoting ER-mitochondria Ca2+ transfer and apoptosis, linked IRBIT to programmed cell death.

    Evidence MAM fractionation, co-IP, Ca2+ release and apoptosis assays, dephosphorylation studies

    PMID:27995898

    Open questions at the time
    • In vivo relevance of IRBIT-Bcl2l10 axis in apoptosis not validated in animal models
    • Identity of phosphatase responsible for apoptotic dephosphorylation of IRBIT unknown
  11. 2018 High

    Detailed phosphoproteomic dissection of how IRBIT recruits PP1, SPAK, calcineurin, and CaMKII to control distinct phosphorylation sites on NBCe1-B that govern chloride sensitivity and active conformation revealed IRBIT as a multi-kinase/phosphatase scaffolding hub for transporter fine-tuning.

    Evidence Phosphoproteomics, systematic mutagenesis, electrophysiology, co-IP

    PMID:30377224

    Open questions at the time
    • Whether the same multi-kinase scaffold operates on other IRBIT-regulated transporters not shown
    • Structural basis of simultaneous scaffolding unknown
  12. 2020 High

    Establishing that the IRBIT-RNR circuit controls intestinal stem cell differentiation in Drosophila, and that IRBIT activates NBCe1-B by competitively displacing the AID from the transmembrane domain via electrostatic interaction, refined both the developmental and biophysical understanding of IRBIT function.

    Evidence Drosophila genetic loss-of-function for RNR regulation; systematic charge-swap mutagenesis and electrophysiology in Xenopus oocytes for AID displacement mechanism

    PMID:32179478 PMID:33237573

    Open questions at the time
    • Mammalian stem cell relevance of IRBIT-RNR axis not tested
    • Whether AID displacement mechanism generalizes to other autoinhibited transporters unknown
  13. 2021 High

    Discovery that AHCYL1 senses S-adenosyl-L-homocysteine via its C-terminus to inhibit PIK3C3 and suppress autophagy independently of MTORC1 revealed IRBIT as a metabolite sensor linking one-carbon metabolism to autophagy.

    Evidence SAH binding assays, PIK3C3 activity assays, autophagy assays, in vivo validation

    PMID:33993848

    Open questions at the time
    • Whether SAH-sensing and IP3R regulation are coordinated or independent is unknown
    • Structural basis of SAH binding to C-terminus not resolved
  14. 2025 Medium

    Identification of NAD redox state as a modulator of IRBIT-dependent NBCe1-B activation, PREX2/RAC1 GEF activity enhancement by AHCYL1, and the IRBIT/LIMA1/DRA complex for stimulus-dependent Cl−/HCO3− exchange further expanded the scope of IRBIT as a context-dependent signaling integrator.

    Evidence Electrophysiology with NAD+/NADH modulation; LC-MS/MS pulldown with in vitro GEF assay; co-IP with siRNA knockdown and DRA activity measurements

    PMID:39985648 PMID:40365293 PMID:40569378

    Open questions at the time
    • Physiological contexts where NAD redox state controls IRBIT function not defined
    • PREX2 interaction validated only in NSCLC, generalizability unknown
    • LIMA1-IRBIT-DRA complex structure and stoichiometry unresolved
  15. 2026 High

    Definitive mapping of CK2-phosphorylated S80/S84/S85 as the primary IP3R-binding determinants of IRBIT, with computational modeling showing these residues mimic IP3 in the binding core, resolved a long-standing question about which phosphosites are directly responsible for pseudoligand function.

    Evidence In vitro kinase assays (PKA, CK2), pulldown with phosphomimetic mutants, Ca2+ imaging in living cells, computational docking

    PMID:42032162

    Open questions at the time
    • Experimental high-resolution structure of IRBIT-IP3R complex not yet obtained
    • How CK2 and PKA phosphorylation are coordinated in vivo remains unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of IRBIT's simultaneous scaffolding of multiple kinases/phosphatases, how IRBIT partitions among its many targets (IP3R, transporters, RNR, PAP, PIK3C3) in different cell types, and whether IRBIT loss-of-function causes a defined human Mendelian disorder.
  • No high-resolution structure of any IRBIT complex
  • Target prioritization mechanism across diverse binding partners unknown
  • No human genetic disease linked to AHCYL1 mutations identified in the literature

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 9 GO:0060090 molecular adaptor activity 6
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-382551 Transport of small molecules 9 R-HSA-162582 Signal Transduction 8 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
BCL2L10CFTRITPR1PIK3C3PPP1CARRM1SLC4A4SLC9A3
Complex memberships
IRBIT-CPSF/Fip1 complexIRBIT-IP3R complexIRBIT-RNR complex

Evidence

Reading pass · 33 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 is essential for the interaction, and the IRBIT binding region on IP3R1 was mapped to the IP3 binding core. Alkaline phosphatase treatment abolished the interaction, indicating that phosphorylation of IRBIT is required for binding. Affinity purification, in vitro binding assays, co-immunoprecipitation, alkaline phosphatase treatment The Journal of biological chemistry High 12525476
2006 IRBIT competes with IP3 for the common binding site on IP3R, suppressing IP3R activation. Multiserine phosphorylation of IRBIT is essential for binding to IP3R, and 10 of 12 key amino acids in IP3R for IP3 recognition also participate in IRBIT binding, establishing IRBIT as an endogenous pseudoligand of IP3R. [3H]IP3 binding assays, in vitro Ca2+ release assays, Ca2+ imaging in intact cells, mutagenesis Molecular cell High 16793548
2006 IRBIT directly interacts with IP3R, requiring both the suppressor domain and the IP3-binding core of IP3R for strong interaction. A PEST motif and PDZ-ligand on IRBIT are critical for IP3R interaction, and Asp-73 is a critical residue. IRBIT inhibits both IP3 binding and IP3-induced Ca2+ release. Direct binding assays, deletion and point mutagenesis, IP3 binding competition, Ca2+ release assays Biochemical and biophysical research communications High 16527252
2006 IRBIT specifically binds to the pancreas-type NBC1 (pNBC1) but not kidney-type NBC1 (kNBC1), through the N-terminal pNBC1-specific domain. IRBIT binding depends on phosphorylation of multiple serine residues of IRBIT. Co-expression of IRBIT in Xenopus oocytes is required for pNBC1 to manifest substantial electrogenic activity, revealing IRBIT as an activator of pNBC1. 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 PP1-binding site on IRBIT (preceding the PEST domain), dephosphorylates Ser68 of IRBIT, and thereby reduces IRBIT's affinity for IP3R. Phosphorylation of Ser68 is required for subsequent phosphorylation of Ser71 and Ser74, and Ser71/Ser74 phosphorylation is sufficient to enable IRBIT-mediated inhibition of IP3 binding. IRBIT thus acts as a substrate specifier for PP1. In vitro binding assays, mass spectrometry, site-directed mutagenesis, phosphatase assays, Co-IP The Biochemical journal High 17635105
2008 IRBIT activates both basolateral pNBC1 and luminal CFTR in pancreatic duct to coordinate fluid and HCO3- secretion. siRNA knockdown of IRBIT markedly inhibited ductal pNBC1 and CFTR activities, luminal Cl- absorption, HCO3- secretion, and fluid secretion. IRBIT activates pNBC1 via the PEST domain alone, while activation of CFTR requires multiple IRBIT domains, indicating distinct mechanisms. siRNA knockdown, video microscopy, ion-selective microelectrodes, single-channel recordings, expression of IRBIT domain constructs in HEK cells The Journal of clinical investigation High 19033647
2008 IRBIT binds to the C-terminal domain of NHE3 and activates NHE3 activity in a Ca2+-dependent manner. IRBIT-dependent activation of NHE3 involves exocytic trafficking of NHE3 to the plasma membrane, requires calmodulin and CaMKII, and can reverse NHERF2-dependent inhibition of NHE3. Co-immunoprecipitation, ectopic expression, siRNA knockdown, NHE3 activity assays, cell surface biotinylation, pharmacological inhibition The Journal of biological chemistry High 18829453
2009 IRBIT interacts with CPSF (cleavage and polyadenylation specificity factor), with the primary target being Fip1 subunit, in a phosphorylation-dependent manner. IRBIT is recruited to polyadenylation signal-containing RNA. Phosphorylation of IRBIT's serine-rich region promotes cytoplasmic redistribution of Fip1. IRBIT also binds poly(A) polymerase (PAP) and inhibits PAP activity in a phosphorylation-dependent manner. Co-immunoprecipitation, in vitro binding assays, RNA pulldown, PAP activity assay, immunofluorescence The Journal of biological chemistry High 19224921
2009 Long-IRBIT (AHCYL2), an IRBIT homologue, heteromerizes with IRBIT but retains little ability to interact with IP3R despite conserving critical amino acids. The unique N-terminal appendage (LISN domain) of Long-IRBIT inhibits its interaction with IP3R. Long-IRBIT and IRBIT show distinct distributions in mouse cerebellar cortex. Co-immunoprecipitation, deletion mutagenesis, immunohistochemistry Journal of neurochemistry Medium 19220705
2010 IRBIT mediates angiotensin II (ANG II)-induced activation of NHE3 via CaMKII-dependent phosphorylation. ANG II transiently increases IRBIT binding to NHE3, and inhibition of CaMKII blocks both ANG II-induced IRBIT-NHE3 binding and NHE3 surface abundance. Mutations of Ser-68, Ser-71, and Ser-74 of IRBIT decreased binding to NHE3 and reduced NHE3 activity. siRNA knockdown, overexpression, co-immunoprecipitation, NHE3 activity assays, CaMKII inhibition, site-directed mutagenesis The Journal of biological chemistry High 20584908
2011 IRBIT activates NBCe1-B (pNBC1) by relieving autoinhibition. Deletion of the autoinhibitory domain (AID, residues ~1-87) stimulates NBCe1-B to the same extent as coexpression of wild-type IRBIT. An NBCe1-B construct lacking residues 2-16 is fully autoinhibited but cannot be stimulated by IRBIT, indicating IRBIT-binding and autoinhibitory determinants are distinct but overlapping. Two-electrode voltage clamp in Xenopus oocytes, deletion mutagenesis American journal of physiology. Cell physiology High 22012331
2011 IRBIT governs epithelial secretion by antagonizing the WNK/SPAK kinase pathway. WNK kinases act as scaffolds to recruit SPAK, which phosphorylates CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposes this by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their surface expression and activity. Silencing of both SPAK and IRBIT rescues the secretion defect caused by IRBIT silencing alone. siRNA knockdown, phosphoprotein analysis, co-immunoprecipitation, epithelial secretion assays, genetic epistasis The Journal of clinical investigation High 21317537
2012 IRBIT interacts with the Cl-/HCO3- exchanger AE2; IRBIT binding facilitates lysosomal degradation of AE2, while coexisting L-IRBIT inhibits this degradation, resulting in opposing regulation of AE2 expression and activity. This affects regulatory volume increase and cell migration. Co-immunoprecipitation, KO cell lines, AE2 activity assays, lysosome inhibitor (bafilomycin A1), cell migration assays Scientific reports Medium 33727633
2013 IRBIT mediates synergy between Ca2+ and cAMP signaling pathways in pancreatic and salivary duct epithelial cells. cAMP-induced phosphorylation of IP3Rs reduces their affinity for Irbit, allowing weak IP3 production to release Irbit from IP3Rs; Irbit then translocates to CFTR and Slc26a6 in the plasma membrane to stimulate secretion. This synergy was absent in Irbit-/- and Slc26a6-/- mice and in mice with IP3Rs mutated at PKA phosphorylation sites. Knockout mouse models, immunoprecipitation, intracellular pH measurements, Cl- current recordings, fluid secretion assays, genetic epistasis Gastroenterology High 23542070
2013 A conserved positively charged module within NBCe1-B (residues 37-65) is required for interaction and activation of NBCe1-B and NBCn1-A by IRBIT and for regulation by PIP2. IRBIT and PIP2 activate these transporters in a nonadditive but complementary manner. Phosphorylation of Ser65 mediates SPAK regulation while Thr49 is required for IRBIT and SPAK regulation. The same regulatory module was identified in CFTR R domain and Slc26a6 STAS domain, and IRBIT binds these domains. Mutagenesis, Co-IP, electrophysiology in Xenopus oocytes Proceedings of the National Academy of Sciences of the United States of America High 23431199
2014 IRBIT forms a deoxyadenosine triphosphate (dATP)-dependent complex with ribonucleotide reductase (RNR) in metazoans, stabilizing dATP in the activity site of RNR and inhibiting the enzyme. Formation of the RNR-IRBIT complex is regulated by phosphorylation of IRBIT. Ablation of IRBIT in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression. Co-immunoprecipitation, in vitro RNR activity assays, phosphorylation analysis, dNTP pool measurement, cell cycle analysis in IRBIT-depleted cells Science (New York, N.Y.) High 25237103
2015 IRBIT binds CaMKIIα and suppresses its kinase activity by inhibiting calmodulin binding to CaMKIIα. In IRBIT-deficient mice, TH phosphorylation by CaMKIIα is increased in the ventral tegmental area, leading to elevated catecholamine levels, increased locomotor activity, and social abnormalities. Co-immunoprecipitation, kinase activity assays, IRBIT-deficient mice, behavioral analysis, phosphorylation assays Proceedings of the National Academy of Sciences of the United States of America High 25922519
2015 IRBIT interacts with all PIPK isoforms in heterologous systems and specifically with PIPKIα and PIPKIIα in mouse cerebellum. Two conserved catalytic aspartate residues of PIPKIα and PIPKIIα are required for IRBIT binding. Phosphatidylinositol 4-phosphate, Mg2+, and/or ATP interfere with the interaction. Mutations in the serine-rich region of IRBIT affect selectivity for PIPKIα versus PIPKIIα. IRBIT, PIPKIα, and NBCe1-B form a signaling complex. Co-immunoprecipitation, in vitro binding assays, site-directed mutagenesis, immunocytochemistry PloS one Medium 26509711
2016 IRBIT interacts with the Bcl-2 homolog Bcl2l10, and together they exert additive inhibition of IP3R in the physiological state. IRBIT and Bcl2l10 associate in mitochondria-associated membranes (MAMs). Upon apoptotic stress, IRBIT is dephosphorylated and becomes an inhibitor of Bcl2l10; IRBIT also promotes ER-mitochondria contact, facilitating massive Ca2+ transfer to mitochondria and promoting apoptosis. Co-immunoprecipitation, fractionation (MAM isolation), Ca2+ release assays, apoptosis assays, dephosphorylation studies eLife High 27995898
2016 NHERF1 PDZ1 domain interacts with IRBIT and is required for ANG II-mediated forward trafficking and activation of NHE3. IRBIT phosphorylation at Ser68 is necessary for assembly of the NHERF1-IRBIT-NHE3 complex, and IRBIT is indispensable for ANG II-induced increase in NHERF1-NHE3 interaction. Co-immunoprecipitation, overexpression of dominant negative constructs, surface NHE3 quantification, site-directed mutagenesis American journal of physiology. Renal physiology Medium 27279487
2017 IRBIT and Long-IRBIT form homo- and heteromultimers. N-terminal splicing of Long-IRBIT changes protein stability and selectivity toward target molecules. Different combinations of IRBIT family multimers contribute to functional diversity. Co-immunoprecipitation, expression analysis in multiple tissues, mutagenesis of N-terminal regions Proceedings of the National Academy of Sciences of the United States of America Medium 28348216
2018 IRBIT recruits PP1 and SPAK to control phosphorylation of Ser65 in NBCe1-B, affecting Cl-in sensing by the 32GXXXP36 motif. IRBIT also recruits calcineurin and CaMKII to control phosphorylation of Ser12, affecting Cl-in sensing by 194GXXXP198. Phosphorylation of Ser232, Ser233, and Ser235 determines the active vs. inactive conformation of NBCe1-B, with the pSer233/pSer235 form mimicking IRBIT-activated NBCe1-B but insensitive to Cl-in inhibition. Phosphoproteomic analysis, mutagenesis, electrophysiology, co-immunoprecipitation Science signaling High 30377224
2020 IRBIT activates NBCe1-B by releasing the autoinhibitory domain (AID) from the transmembrane domain. The AID (residues 40-85) acts as a brake binding the transmembrane domain via electrostatic interaction; IRBIT competitively binds the AID to release this brake. The IRBIT-binding domain of NBCe1-B consists of negatively charged (residues 1-24) and positively charged (residues 40-52) arms. Negatively charged Asp/Glu residues plus Ser/Thr residues in IRBIT PEST domain are required for NBCe1-B interaction. Electrophysiology (Xenopus oocytes), systematic mutagenesis, charge manipulation experiments The Journal of physiology High 33237573
2020 IRBIT regulates ribonucleotide reductase (RNR) activity in Drosophila ISC progeny, and IRBIT expression directs differentiation of intestinal stem cell progeny by suppressing RNR activity. Disruption of the IRBIT-RNR circuit causes premature loss of intestinal tissue integrity; age-related dysplasia can be reversed by suppressing RNR in ISC progeny. Genetic loss-of-function in Drosophila, tissue histology, RNR activity assays iScience Medium 32179478
2020 IRBIT stabilizes NBCn1 transporter expression in the plasma membrane and enhances cancer cell migration. Overexpression of IRBIT enhanced NBCn1 activity and cell migration; knockdown of IRBIT or NBCn1 attenuated cell migration. EGF signaling recruits IRBIT to maintain NBCn1 in the plasma membrane. Overexpression, siRNA knockdown, NBC activity assays, cell migration assays, surface protein analysis Pharmaceutics Medium 32867284
2021 AHCYL1 (IRBIT) functions as a SAH (S-adenosyl-L-homocysteine) sensor to inhibit autophagy through PIK3C3. The C-terminus of AHCYL1 specifically binds SAH, and this interaction promotes binding of the N-terminus to the catalytic domain of PIK3C3, inhibiting PIK3C3 activity and thus suppressing autophagy in an MTORC1-independent manner. Co-immunoprecipitation, PIK3C3 activity assays, autophagy assays, SAH binding experiments, in vivo validation Autophagy High 33993848
2022 IRBIT physically interacts with microtubule-associated protein tau in brain tissues and cultured cells. Tau overexpression modifies the close localization of AHCYL1/IRBIT to IP3R at the endoplasmic reticulum, as shown by proximity ligation assay. Protein microarray, co-immunoprecipitation, proximity ligation assay The Journal of biological chemistry Medium 35218773
2022 IRBIT knockout in INS-1 cells reduces insulin content and glucose-stimulated insulin secretion, reduces INS2 mRNA levels, and increases nuclear localization of AHCY. In RyR2 KO cells, IRBIT protein levels are reduced, suggesting RyR2 maintains IRBIT levels. IRBIT and RyR2 deletion causes increased exon 2 methylation of insulin genes. CRISPR knockout, insulin secretion assays, qPCR, nuclear fractionation, DNA methylation analysis, proteomics Scientific reports Medium 35562179
2024 AHCYL1 deficiency in NRAS-mutant melanoma results in decreased ER calcium levels, activation of the unfolded protein response (UPR), and downstream apoptosis. AHCYL1 transcription in NRAS-mutated melanoma is regulated by ATF2. AHCYL1 is selectively upregulated and required for cell proliferation specifically in NRAS-mutated (not BRAF V600E) melanoma. RNAi screen, AHCYL1 knockdown, Ca2+ measurements, UPR assays, apoptosis assays, xenograft models Molecular cancer research : MCR Medium 38294692
2025 IRBIT activates NBCe1-B in a NAD redox state-dependent manner; IRBIT and L-IRBIT serve as NAD cofactors, with NAD+ enhancing and NADH decreasing NBCe1-B activity. Blocking the NAD salvage pathway greatly decreases NBCe1-B activation by the IRBITs, establishing NAD redox state as a modulator of IRBIT-dependent transporter regulation. Electrophysiology, pharmacological inhibition of NAD salvage pathway, NAD+/NADH administration Science China. Life sciences Medium 39985648
2025 AHCYL1 enhances PREX2 GEF (guanine nucleotide exchange factor) activity toward RAC1 by alleviating mutual inhibition between PREX2 and PTEN, thereby intensifying tumor-promoting effects of PREX2 in NSCLC. AHCYL1 was identified as a novel PREX2-interacting protein. Pull-down assay, LC-MS/MS, in vitro GEF assay, active RAC1 pulldown assay, western blotting Theranostics Medium 40365293
2025 IRBIT and LIMA1 form a complex with SLC26A3 (DRA) that is required for acute cAMP/Ca2+-stimulated activation of DRA, but not for basal DRA activity. IRBIT is indispensable for maximum ATP-stimulated (but not forskolin-only) DRA activation and for the cAMP/ATP-induced elevation of intracellular Ca2+. cAMP/ATP stimulation increases co-precipitation of LIMA1 with both IRBIT and DRA and increases brush-border DRA and IRBIT abundance. Co-immunoprecipitation, siRNA knockdown, intracellular pH measurements (DRA activity), surface protein analysis, Ca2+ measurements American journal of physiology. Cell physiology Medium 40569378
2026 Phosphorylation of IRBIT at S80, S84, and S85 provides the primary binding sites for the IP3-binding core (IBC) of IP3R. S68 is the predominant phosphorylation site on IRBIT but is not required for IP3R binding. PKA phosphorylates S62/S64/S66 and CK2 phosphorylates S80/T82/S84/S85 of IRBIT. The phosphorylated S80/S84/S85 peptide computationally binds IBC similarly to IP3, and IRBIT-S68A/S80D/S84D/S85D was sufficient to suppress IP3R-mediated Ca2+ release in living cells. In vitro kinase assays, pulldown assays, Ca2+ imaging, site-directed mutagenesis, computational modeling Communications biology High 42032162

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 141 16769890
2006 IRBIT suppresses IP3 receptor activity by competing with IP3 for the common binding site on the IP3 receptor. Molecular cell 140 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 109 19033647
2011 IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway. The Journal of clinical investigation 86 21317537
2013 Irbit mediates synergy between ca(2+) and cAMP signaling pathways during epithelial transport in mice. Gastroenterology 79 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
2016 IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact. eLife 62 27995898
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 62 18829453
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.) 44 25237103
2014 IRBIT: a regulator of ion channels and ion transporters. Biochimica et biophysica acta 39 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 37 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 28 23145124
2021 AHCYL1 senses SAH to inhibit autophagy through interaction with PIK3C3 in an MTORC1-independent manner. Autophagy 27 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
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
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.) 5 35351819
2012 The discovery and structural investigation of the IP₃ receptor and the associated IRBIT protein. Advances in experimental medicine and biology 5 22453947
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 Cardiac hypertrophy induced by overexpression of IP3-released inositol 1, 4, 5-trisphosphate receptor-binding protein (IRBIT). Journal of molecular and cellular cardiology 3 39929439
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
2026 Deciphering the multi-site phos-code of IRBIT underlying its binding to IP3R. Communications biology 0 42032162
2025 AHCYL1 mediates the tumor-promoting effect of PREX2 in non-small cell lung carcinoma. Theranostics 0 40365293
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