Affinage

ITM2B

Integral membrane protein 2B · UniProt Q9Y287

Length
266 aa
Mass
30.3 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ITM2B/BRI2 is a type II transmembrane protein that physiologically suppresses amyloidogenic processing and supports synaptic function in the brain (PMID:18753367, PMID:30890756). Mature BRI2 reaches the plasma membrane and endosomes and binds APP in cis through their transmembrane domains, sterically restricting alpha-, beta-, and gamma-secretase access to APP and thereby lowering Abeta production (PMID:15983050, PMID:16027166, PMID:19748705); genetic loss of BRI2 raises Abeta in vivo while overexpression lowers it (PMID:18753367, PMID:18524908). BRI2 also broadens its amyloid-suppressing reach by reducing BACE1 levels, by acting as a receptor that elevates secreted insulin-degrading enzyme, and by directly binding TREM2 in microglia to limit its alpha-secretase processing (PMID:23701002, PMID:21873424, PMID:38347225). BRI2 is matured by sequential proteolysis: furin cleaves the C-terminus to liberate the anti-aggregant Bri2-23 peptide, ADAM10 sheds the BRICHOS ectodomain, and SPPL2a/SPPL2b carry out intramembrane cleavage of the residual N-terminal fragment (PMID:11193182, PMID:11709554, PMID:17965014, PMID:18524908). The released BRICHOS domain is an assembly-state-dependent chaperone whose monomers block Abeta42 neurotoxicity, dimers suppress fibril formation, and oligomers inhibit non-fibrillar aggregation, with activity extending to IAPP (PMID:29234026, PMID:31959875, PMID:29507232). BRI2 function and trafficking are tuned by N-glycosylation at Asn170, by a BRI2:PP1 phosphorylation complex that governs neuritogenesis, and by NRBP1-containing CRL2/CRL4A-mediated ubiquitin degradation (PMID:21752865, PMID:26515131, PMID:32160551). The familial British and Danish dementia mutations cause C-terminal stop-loss/frameshift extensions that release the amyloidogenic ABri and ADan peptides via the same furin step while drastically reducing mature functional BRI2 at synapses, establishing loss of BRI2 synaptic function—impaired glutamate release and AMPAR responses—as a pathogenic mechanism independent of amyloid deposition (PMID:10391242, PMID:10781099, PMID:21048150, PMID:33172889).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Established how a BRI2 disease mutation produces amyloid, answering what molecular lesion underlies familial British dementia.

    Evidence Molecular cloning, sequencing, and antibody analysis of isolated amyloid fibrils identifying a stop-codon substitution that extends the ORF and a furin-released 34-residue ABri peptide

    PMID:10391242

    Open questions at the time
    • Did not define BRI2's normal physiological function
    • Did not establish whether amyloid or protein loss drives disease
  2. 2000 High

    Generalized the proteolytic-release mechanism to a second mutation, showing a frameshift duplication produces the ADan amyloid peptide in familial Danish dementia.

    Evidence N-terminal sequencing of patient amyloid fibrils plus molecular genetic analysis

    PMID:10781099

    Open questions at the time
    • Subcellular site of peptide accumulation not resolved
    • Normal BRI2 function still unknown
  3. 2000 High

    Identified furin as the constitutive protease cleaving BRI2 and showed mutant precursor yields elevated peptide, defining the enzymatic step that liberates the C-terminal peptides.

    Evidence Cell-based expression of BRI/BRI-L with furin inhibitor and comparison across proprotein convertases; replicated subcellular localization showing ADan accumulates intracellularly

    PMID:11193182 PMID:11709554

    Open questions at the time
    • Did not address whether furin processing is regulated
    • Other proteolytic steps not yet identified
  4. 2002 Medium

    Proposed a pro-apoptotic role for a short ITM2B isoform, raising the question of whether BRI2 participates in cell death regulation.

    Evidence Overexpression of ITM2B(s), Co-IP with Bcl-2, and BH3-domain mutagenesis with viability assays

    PMID:12082633

    Open questions at the time
    • Physiological relevance of the short isoform not established
    • Not linked to the neuronal/synaptic functions later defined
    • Single lab, not independently confirmed
  5. 2005 High

    Revealed BRI2's normal function as a cis-binding inhibitor of APP, answering how it could suppress Abeta production.

    Evidence Reciprocal Co-IP with deletion mutants mapping the transmembrane interaction and Abeta ELISA/CTF Western blots in cells and primary neurons

    PMID:15983050 PMID:16027166

    Open questions at the time
    • In vivo significance not yet demonstrated
    • Which secretases are blocked at which compartments unresolved
  6. 2007 High

    Defined the full maturation pathway by identifying ADAM10 ectodomain shedding followed by SPPL2a/SPPL2b intramembrane cleavage.

    Evidence Systematic gain/loss-of-function across all SPP/SPPL family members and dominant-negative ADAM10 with Western blot fragment readouts

    PMID:17965014

    Open questions at the time
    • Functions of the released fragments not yet defined
    • Regulation of these cleavages unknown
  7. 2008 High

    Demonstrated in vivo that BRI2 is a physiological Abeta suppressor and that the furin-released Bri2-23 peptide mediates the anti-amyloidogenic effect.

    Evidence BRI2 knockout and transgenic overexpression in AD mouse models, in vitro Abeta aggregation assays, secretase-access assays, and CSF peptide detection

    PMID:18524908 PMID:18753367

    Open questions at the time
    • Did not separate amyloid-suppression from any independent BRI2 functions
    • Synaptic role not addressed
  8. 2009 High

    Refined the mechanism to mature BRI2 acting at the plasma membrane/endosomes, and showed BRI2 homodimerizes via Cys89.

    Evidence FRAP imaging, maturation-discriminating Co-IP and fractionation, and Cys89 mutagenesis on non-reducing gels

    PMID:18440095 PMID:19748705

    Open questions at the time
    • Functional consequence of dimerization for APP inhibition not defined
    • Dimerization data from single lab
  9. 2010 High

    Separated amyloid deposition from disease by showing the British mutation reduces mature BRI2 and that haploinsufficiency alone causes memory deficits.

    Evidence FBD knock-in and Bri2+/- heterozygous mice with behavioral testing and Western blots in mouse and human FBD brain

    PMID:21048150

    Open questions at the time
    • Molecular basis of the memory deficit not yet mapped to a pathway
    • Synaptic mechanism not resolved
  10. 2011 High

    Established genetic epistasis placing APP metabolites downstream of BRI2 loss in synaptic/memory pathology and added trafficking, IDE, and BACE1 regulatory layers.

    Evidence FDD-KI x APP-heterozygous cross with LTP and behavior; Asn170 glycosylation mutagenesis with biotinylation/pulse-chase; IDE deletion-construct experiments; BRICHOS-Abeta binding/ThT assays

    PMID:20036644 PMID:21587206 PMID:21752865 PMID:21873424 PMID:22194595

    Open questions at the time
    • Relative contributions of direct APP inhibition vs IDE/BACE1 routes not quantified
    • Some regulatory mechanisms from single labs
  11. 2013 Medium

    Showed BRI2 lowers BACE1 by promoting lysosomal degradation and reducing its mRNA, broadening how BRI2 limits beta-cleavage of APP.

    Evidence Co-IP, lysosomal/proteasomal inhibitor experiments, BACE1 RT-PCR, and sAPPbeta Western blotting

    PMID:23701002

    Open questions at the time
    • Mechanism linking BRI2 to BACE1 transcription unknown
    • Single lab
  12. 2017 High

    Resolved BRICHOS chaperone behavior as assembly-state-dependent and linked phosphorylation to processing and neuritogenesis.

    Evidence Recombinant BRICHOS in defined oligomeric states with ThT, hippocampal network electrophysiology, Drosophila, and EM; PP1-binding-motif mutagenesis with neurite assays

    PMID:28176357 PMID:29234026

    Open questions at the time
    • In vivo relevance of specific BRICHOS assembly states not fully established
    • Phosphorylation findings from single lab
  13. 2018 High

    Extended BRICHOS chaperone activity to IAPP and showed endogenous Bri2 protects beta cells from amyloid toxicity, indicating a general anti-amyloid function.

    Evidence siRNA knockdown and BRICHOS overexpression in human beta cells and Drosophila, in vitro ThT, and colocalization

    PMID:29507232

    Open questions at the time
    • Endogenous relevance to diabetes pathology in humans not established
    • Mechanism of intracellular Bri2-IAPP colocalization unclear
  14. 2019 Medium

    Defined dual presynaptic and postsynaptic roles for ITM2B in glutamatergic transmission and added a candidate non-amyloid interactor, GLUT9.

    Evidence Cell-type-specific conditional Itm2b knockout in CA3/CA1 with electrophysiology; dual-membrane Y2H and Co-IP plus urate transport assays for GLUT9

    PMID:30890756 PMID:31695625

    Open questions at the time
    • Molecular effector linking BRI2 to glutamate release and AMPAR responses unknown
    • GLUT9 interaction from single lab without in vivo confirmation
  15. 2020 High

    Unified loss-of-function as the disease mechanism by showing FDD/FBD mutations reduce mature synaptic BRI2 and phenocopy knockout; identified NRBP1-CRL ubiquitin degradation and augmentable BRICHOS chaperone state.

    Evidence FDD/FBD knock-in mice with maturation assays and hippocampal-slice electrophysiology; NRBP1 CRL component MS/Co-IP/ubiquitination with Abeta readout; R221E BRICHOS monomerization with AUC and electrophysiology

    PMID:31959875 PMID:32160551 PMID:33172889

    Open questions at the time
    • Upstream signals regulating NRBP1-mediated BRI2 turnover unknown
    • Therapeutic feasibility of modulating BRICHOS assembly in vivo untested
  16. 2024 High

    Expanded BRI2's substrate repertoire to TREM2 in microglia and identified MBP as a regulator of furin processing and trafficking.

    Evidence Cell-free recombinant ectodomain binding, constitutive and microglial-specific Itm2b knockouts, scRNA-seq, and TREM2 processing readouts; MBP-Bri2 molecular dynamics plus co-expression cell assays

    PMID:38347225 PMID:38473856

    Open questions at the time
    • Functional consequence of BRI2-TREM2 regulation for microglial biology not fully defined
    • MBP regulation mechanism from a single in silico/cell study
  17. 2025 High

    Provided a sequence-level mechanism for pathogenic stop-loss mutations by mapping the ADan amyloid core and showing the Bri2 C-terminus harbors an incomplete amyloid motif that becomes amyloidogenic on extension.

    Evidence Massively parallel yeast-based amyloid assay scoring hundreds of ADan substitutions and thousands of random C-terminal extensions

    PMID:40314981

    Open questions at the time
    • Yeast amyloid scores require validation in mammalian/neuronal context
    • Does not address how extension interacts with the loss-of-function pathway

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular effectors that couple BRI2 to presynaptic glutamate release and postsynaptic AMPAR responses, and how its many regulatory inputs are integrated in vivo, remain undefined.
  • No identified synaptic effector downstream of BRI2
  • No structure of the BRI2-APP transmembrane complex
  • Physiological balance among APP, TREM2, IDE, BACE1, and GLUT9 interactions not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0044183 protein folding chaperone 3 GO:0140313 molecular sequestering activity 3 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 3 GO:0005576 extracellular region 2 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-112316 Neuronal System 2 R-HSA-168256 Immune System 1
Partners
ADAM10APPBACE1BCL2NRBP1PP1SLC2A9TREM2
Complex memberships
BRI2-APP transmembrane complexBRI2:PP1 complexNRBP1 CRL2/CRL4A ubiquitin ligase

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 A single base substitution at the stop codon of BRI generates a longer open reading frame producing a 277-residue precursor; furin-like proteolytic cleavage releases the 34 C-terminal amino acids as the ABri amyloid peptide, establishing the mechanism by which the FBD mutation causes amyloid generation. Molecular cloning, sequencing, restriction enzyme analysis, antibody characterization of isolated amyloid fibrils Nature High 10391242
2000 A 10-nucleotide duplication in the 3' region of BRI2 causes a frameshift generating a larger precursor; furin cleavage releases the 34 C-terminal amino acid ADan peptide, which is deposited as amyloid in familial Danish dementia, establishing the same proteolytic release mechanism for a second BRI2 mutation. N-terminal sequence analysis of isolated amyloid fibrils, molecular genetic analysis, sequencing Proceedings of the National Academy of Sciences of the United States of America High 10781099
2000 BRI2 is constitutively processed by furin, which cleaves between residues 243 and 244 to release the C-terminal peptide; furin is the most efficient proprotein convertase for this processing, and the mutant BRI-L precursor generates elevated levels of peptides compared to wild-type. Cell-based expression of BRI and BRI-L with furin inhibitor (alpha1-antitrypsin Portland), comparison of multiple proprotein convertases (furin, PACE4, PC6A, PC6B, LPC) Annals of the New York Academy of Sciences High 11193182 11709554
2001 Furin processes both BRI and BRI-L (FBD mutant) and BRI-D (FDD mutant); the ADan peptide accumulates predominantly in intracellular compartments whereas ABri is detected both intracellularly and in the medium, suggesting intracellular accumulation drives neuronal damage. Inducible expression with furin inhibitor alpha1-antitrypsin Portland, comparison of proprotein convertases, intracellular/extracellular peptide detection The Journal of biological chemistry High 11709554
2005 BRI2 physically interacts with APP (amyloid-beta precursor protein); the interaction requires the transmembrane domain region (residues 648–719 of APP751 and residues 46–106 of BRI2), occurs in cis on the same cell membrane, and BRI2 expression inhibits APP processing, reducing secreted Abeta and AID levels. Co-immunoprecipitation in transfected and non-transfected cells, deletion mutagenesis, Abeta ELISA The Journal of biological chemistry High 15983050 16027166
2005 BRI2 interacts with APP via regions encompassing their full transmembrane domains; BRI2 presence increases cellular APP levels and beta-secretase-generated CTFs while decreasing alpha-secretase-generated CTFs and total secreted Abeta, indicating BRI2 modulates secretase access to APP. Co-immunoprecipitation in transfected HEK cells and primary neurons, deletion mutagenesis, Western blotting of APP processing fragments The Journal of biological chemistry High 16027166
2007 BRI2 undergoes regulated intramembrane proteolysis: (1) ADAM10 sheds the BRI2 ectodomain (BRICHOS domain) into the extracellular space; (2) the remaining membrane-bound N-terminal fragment is then cleaved intramembranally by SPPL2a and SPPL2b (but not SPP or SPPL3), producing an intracellular domain and a secreted low-molecular-weight C-terminal peptide. Expression of all SPP/SPPL family members including loss-of-function variants in cells, Western blotting, co-expression with dominant-negative ADAM10 The Journal of biological chemistry High 17965014
2008 BRI2 restricts docking of gamma-secretase to APP and blocks alpha- and beta-secretase access to their APP cleavage sequences; gene targeting (BRI2 knockout) increases Abeta levels in AD mouse models while transgenic BRI2 overexpression reduces them, establishing BRI2 as a physiological suppressor of Abeta production. Gene targeting (knockout mice), transgenic overexpression, in vivo Abeta quantification, cell-based secretase access assays The Journal of neuroscience High 18753367
2008 Wild-type BRI2 reduces cerebral Abeta deposition in APP mouse models; the 23 amino acid peptide Bri2-23, released from BRI2 by normal furin processing, is present in human CSF, inhibits Abeta aggregation in vitro, and mediates the anti-amyloidogenic effect in vivo. Somatic brain transgenics, in vitro Abeta aggregation assay, CSF peptide detection The Journal of neuroscience High 18524908
2008 BRI2 forms homodimers in cells via both non-covalent interactions and disulfide bridges between cysteines at position 89; dimers form in the ER and are present at the cell surface and in mouse brain. Non-reducing SDS-PAGE, co-immunoprecipitation, site-directed mutagenesis of Cys89, cell fractionation, mouse brain analysis Neurobiology of aging Medium 18440095
2009 Mature BRI2 (but not immature forms) is transported to the plasma membrane and endosomes where it selectively interacts with mature APP; mature BRI2 inhibits APP processing by alpha-, beta-, and gamma-secretases specifically at the plasma membrane and in endocytic compartments. Live-cell imaging (FRAP), co-immunoprecipitation of mature vs. immature forms, subcellular fractionation, pharmacological inhibition of secretases Neurobiology of aging High 19748705
2009 The extracellular BRICHOS domain of Bri2 (residues 90–236) binds to the ABri23 peptide and to Abeta1-40, and inhibits Abeta1-40 aggregation and fibril formation in vitro. Recombinant protein binding assay, Thioflavin T fibril formation assay Biochemical and biophysical research communications Medium 20036644
2010 The British BRI2 mutation drastically reduces expression of mature BRI2 protein in knock-in mice and in human FBD brains; this loss of BRI2 function causes severe hippocampal memory deficits independently of cerebral amyloidosis or tauopathy, as shown by the identical memory deficit in Bri2+/- heterozygous mice. Knock-in mouse model (FBD-KI), Bri2+/- heterozygous mice, behavioral memory testing, Western blotting for BRI2 protein levels in mouse and human brain The Journal of neuroscience High 21048150
2011 APP/BRI2 complexes are reduced in synaptic membranes of FDD knock-in mice; APP haplodeficiency rescues memory and synaptic plasticity deficits in FDD-KI mice, establishing a functional genetic epistasis between BRI2 and APP in which BRI2 inhibits APP processing and APP metabolites mediate the synaptic/memory pathology. FDD knock-in x APP heterozygous cross (genetic epistasis), co-immunoprecipitation of synaptic membrane fractions, LTP measurements, behavioral memory testing The EMBO journal High 21587206
2011 BRI2 is N-glycosylated at asparagine 170; mutation of Asn170 to alanine reduces BRI2 trafficking to the cell surface and its steady-state plasma membrane levels, but does not affect cleavage by furin or ADAM10. Tunicamycin treatment, site-directed mutagenesis (N170A), cell surface biotinylation, pulse-chase 35S-methionine labeling Glycobiology High 21752865
2011 BRI2 overexpression reduces extracellular Abeta by increasing levels of secreted insulin-degrading enzyme (IDE), a major Abeta-degrading protease; this effect is observed even with BRI2 lacking its C-terminal 23 amino acid peptide, suggesting BRI2 acts as a receptor that regulates IDE secretion. BRI2 overexpression in cells and AD mouse model, IDE ELISA and activity assay, Abeta measurement, BRI2 deletion constructs The Journal of biological chemistry Medium 21873424
2011 The alpha-helical content of the BRI2 transmembrane domain (TMD) governs efficiency of intramembrane cleavage by SPPL2b: higher alpha-helical content reduces cleavage efficiency; a GXXXG dimerization motif has only minor influence; only one of four conserved intramembrane glycine residues significantly affects TMD secondary structure and intramembrane processing. Site-directed mutagenesis of TMD residues, circular dichroism spectroscopy, cell-based cleavage assays The Journal of biological chemistry High 22194595
2013 BRI2 interacts with BACE1 and decreases its cellular levels by promoting lysosomal (not proteasomal) degradation of BACE1; BRI2 also reduces BACE1 mRNA levels by ~50%, thereby reducing beta-cleavage of APP. Co-immunoprecipitation, lysosomal/proteasomal inhibitor experiments, RT-PCR for BACE1 mRNA, Western blotting of sAPPbeta Current Alzheimer research Medium 23701002
2015 BRI2 is a phosphoprotein and a protein phosphatase 1 (PP1) interacting protein; the BRI2:PP1 complex is formed in vitro and in vivo; disruption of the PP1-binding motif increases BRI2 phosphorylation; phosphorylated full-length BRI2 promotes formation of neuritic processes while the BRI2 N-terminal fragment (generated by ADAM10 processing) promotes neurite elongation. Co-immunoprecipitation in vitro and in vivo, PP1-binding motif mutagenesis, phosphorylation assays, ADAM10 inhibitor treatment, neurite outgrowth measurements in SH-SY5Y cells Cellular signalling Medium 26515131
2017 Bri2 BRICHOS domain monomers potently prevent neuronal network toxicity of Abeta42, while dimers strongly suppress Abeta fibril formation; high-molecular-weight oligomers efficiently inhibit non-fibrillar protein aggregation; these qualitatively distinct chaperone activities are governed by the quaternary assembly state of the BRICHOS domain. Recombinant Bri2 BRICHOS in defined oligomeric states, ThT fibril formation assays, hippocampal network oscillation electrophysiology, Drosophila in vivo model, electron microscopy Nature communications High 29234026
2017 BRI2 phosphorylation state (regulated by the BRI2:PP1 complex) is an important regulatory mechanism for its proteolytic processing and neuritogenic role; phosphorylated full-length BRI2 is important for neuritic process formation, while BRI2 NTF (produced by ADAM10 processing) promotes neurite elongation. PP1-binding motif mutant transfection in SH-SY5Y cells, ADAM10 inhibitor treatment, neurite outgrowth quantification, Western blotting Journal of cellular biochemistry Medium 28176357
2018 The BRICHOS domain of Bri2 inhibits IAPP fibril formation in vitro and redirects IAPP into amorphous aggregates; Bri2 colocalizes with IAPP intracellularly in human beta cells; siRNA knockdown of endogenous Bri2 increases sensitivity to metabolic stress and cell death; overexpression of Bri2 BRICHOS is protective against IAPP toxicity in human beta cells and in a Drosophila model. siRNA knockdown, Bri2 overexpression, in vitro ThT fibril assay, cell viability assay, Drosophila survival assay, immunofluorescence colocalization Proceedings of the National Academy of Sciences of the United States of America High 29507232
2019 ITM2B/BRI2 has dual presynaptic and postsynaptic roles in glutamatergic transmission: conditional deletion of Itm2b in CA3 neurons decreases spontaneous glutamate release probability and increases short-term synaptic facilitation, while deletion in CA1 neurons decreases AMPAR-mediated postsynaptic responses. Conditional neuron-specific Cre-mediated Itm2b knockout in hippocampal Schaffer-collateral pathway (CA3, CA1, or both), electrophysiology (spontaneous EPSCs, AMPAR responses, short-term plasticity) Scientific reports High 30890756
2019 ITM2B physically interacts with the urate transporter GLUT9 (SLC2A9), identified by dual-membrane yeast two-hybrid, and confirmed by co-immunoprecipitation in transfected HEK293T cells; ITM2B inhibits GLUT9-mediated urate uptake and stimulates urate efflux; ITM2B variants linked to familial Danish dementia significantly attenuate inhibition of GLUT9-mediated urate influx. Dual-membrane yeast two-hybrid, co-immunoprecipitation in HEK293T cells and Xenopus oocytes, urate transport assays in oocytes, glycosylation mutant analysis Frontiers in physiology Medium 31695625
2020 FDD and FBD pathogenic mutations in ITM2b alter maturation of BRI2 resulting in reduced levels of functional mature BRI2 protein at synapses, leading to reduced spontaneous glutamate release, decreased AMPAR-mediated responses, and increased short-term synaptic facilitation — phenotypes matching those of Itm2b knockout mice, establishing loss of BRI2 synaptic function as a pathogenic mechanism. FDD and FBD knock-in mice, in vivo and in vitro maturation assays, electrophysiology in hippocampal slices The Journal of biological chemistry High 33172889
2020 NRBP1, a substrate receptor of a heterodimeric Cullin-RING ubiquitin ligase (CRL) containing both Cul2 and Cul4A, targets BRI2 (and BRI3) for ubiquitin-mediated degradation; NRBP1 dimerizes and assembles the CRL through its BC-box and cryptic H-box; chaperone-like TSC22D3 and TSC22D4 enhance NRBP1 CRL formation; NRBP1 knockdown in neuronal cells increases BRI2/BRI3 abundance and significantly reduces Abeta production. Co-immunoprecipitation, ubiquitination assays, NRBP1 knockdown in neuronal cells, Abeta ELISA, mass spectrometry interactome Cell reports High 32160551
2020 A R221E mutant of Bri2 BRICHOS forms stable monomers; introducing R221E partially disassembles wild-type Bri2 BRICHOS oligomers into monomers, potentiating their ability to prevent Abeta42 neurotoxicity to neuronal network activity, demonstrating that the chaperone activity of endogenous Bri2 BRICHOS can be augmented by modulating assembly state. Site-directed mutagenesis, analytical ultracentrifugation, hippocampal network oscillation electrophysiology, ThT fibril formation assay Communications biology High 31959875
2002 ITM2B(s), a short cytoplasmic/mitochondrial isoform of ITM2B containing a BH3 domain, induces apoptosis upon IL-2 deprivation and interacts with the anti-apoptotic protein Bcl-2; mutation of the critical L and D residues within the BH3 domain abolishes its pro-apoptotic activity. Cloning and overexpression of ITM2B(s), co-immunoprecipitation with Bcl-2, BH3 domain mutagenesis, cell viability assays Oncogene Medium 12082633
2024 BRI2 directly interacts with TREM2 protein (confirmed by cell-free ectodomain binding with recombinant proteins), inhibits alpha-secretase-mediated TREM2 processing in cells and in vivo; constitutive and microglial-specific Itm2b-KO mice show increased TREM2-CTF and sTREM2; BRI2 also boosts Trem2 mRNA expression and influences Trem2 protein levels through alpha-secretase-independent pathways. Cell-free direct binding of recombinant BRI2 and TREM2 ectodomains, co-immunoprecipitation in heterologous cells, constitutive and conditional (microglial-specific) Itm2b knockout mice, single-cell RNA-sequencing, Western blotting and ELISA for TREM2 processing products EMBO reports High 38347225
2024 Myelin basic protein (MBP) covers a significant portion of the Bri2 ectodomain (including the furin cleavage site) and attenuates furin-mediated Bri2 C-terminal peptide cleavage; MBP co-expression also restricts Bri2 membrane trafficking independently of the furin cleavage suppression. Molecular dynamics simulation of MBP-Bri2 complex, co-expression of MBP with Bri2 and mutants in mammalian cells, Western blotting for processing products, subcellular localization analysis International journal of molecular sciences Medium 38473856
2025 Using a massively parallel yeast-based assay, the amyloid-forming core of ADan fibrils was mapped to positions 20–26 of the C-terminal peptide (where stop-loss extension occurs); ~32% of random C-terminal extensions of Bri2 can nucleate amyloid, showing the Bri2 C-terminus contains an incomplete amyloid motif that becomes amyloidogenic upon extension — providing a mechanism for pathogenic stop-loss mutations. Yeast-based massively parallel amyloid formation assay (676 ADan substitutions and ~18,000 random C-terminal extensions), systematic amyloid scoring Proceedings of the National Academy of Sciences of the United States of America High 40314981

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 386 10391242
2000 A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. Proceedings of the National Academy of Sciences of the United States of America 255 10781099
2007 Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b. The Journal of biological chemistry 137 17965014
2005 The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production. The Journal of biological chemistry 126 15983050
2001 Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia. The American journal of pathology 117 11159188
2005 BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production. The Journal of biological chemistry 101 16027166
2008 BRI2 (ITM2b) inhibits Abeta deposition in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 96 18524908
2008 BRI2 inhibits amyloid beta-peptide precursor protein processing by interfering with the docking of secretases to the substrate. The Journal of neuroscience : the official journal of the Society for Neuroscience 88 18753367
2004 Modulation of GDF5/BRI-b signalling through interaction with the tyrosine kinase receptor Ror2. Genes to cells : devoted to molecular & cellular mechanisms 80 15569154
2017 Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state. Nature communications 71 29234026
2013 Normal cognition in transgenic BRI2-Aβ mice. Molecular neurodegeneration 66 23663320
2009 Maturation of BRI2 generates a specific inhibitor that reduces APP processing at the plasma membrane and in endocytic vesicles. Neurobiology of aging 62 19748705
2003 Expression of BRI, the normal precursor of the amyloid protein of familial British dementia, in human brain. Acta neuropathologica 55 14586629
2018 BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells. Proceedings of the National Academy of Sciences of the United States of America 52 29507232
2008 Cerebral amyloid angiopathy and parenchymal amyloid deposition in transgenic mice expressing the Danish mutant form of human BRI2. Brain pathology (Zurich, Switzerland) 52 18410407
2016 Dementia-related Bri2 BRICHOS is a versatile molecular chaperone that efficiently inhibits Aβ42 toxicity in Drosophila. The Biochemical journal 51 27514716
2010 Memory deficits due to familial British dementia BRI2 mutation are caused by loss of BRI2 function rather than amyloidosis. The Journal of neuroscience : the official journal of the Society for Neuroscience 50 21048150
2020 Augmentation of Bri2 molecular chaperone activity against amyloid-β reduces neurotoxicity in mouse hippocampus in vitro. Communications biology 48 31959875
2020 G-MDSCs-Derived Exosomal miRNA-143-3p Promotes Proliferation via Targeting of ITM2B in Lung Cancer. OncoTargets and therapy 48 33061450
2009 BRI3 inhibits amyloid precursor protein processing in a mechanistically distinct manner from its homologue dementia gene BRI2. The Journal of biological chemistry 48 19366692
2001 Sequence, genomic structure and tissue expression of Human BRI3, a member of the BRI gene family. Gene 48 11290423
2001 Proteolytic processing of familial British dementia-associated BRI variants: evidence for enhanced intracellular accumulation of amyloidogenic peptides. The Journal of biological chemistry 48 11709554
2011 APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant. The EMBO journal 47 21587206
2009 The extracellular domain of Bri2 (ITM2B) binds the ABri peptide (1-23) and amyloid beta-peptide (Abeta1-40): Implications for Bri2 effects on processing of amyloid precursor protein and Abeta aggregation. Biochemical and biophysical research communications 44 20036644
2014 BRI2-BRICHOS is increased in human amyloid plaques in early stages of Alzheimer's disease. Neurobiology of aging 43 24524963
2017 The suppressive effects of Britannin (Bri) on human liver cancer through inducing apoptosis and autophagy via AMPK activation regulated by ROS. Biochemical and biophysical research communications 38 29288670
2011 BRI2 protein regulates β-amyloid degradation by increasing levels of secreted insulin-degrading enzyme (IDE). The Journal of biological chemistry 38 21873424
2006 Genetic alterations of the BRI2 gene: familial British and Danish dementias. Brain pathology (Zurich, Switzerland) 38 16612984
2020 NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation. Cell reports 36 32160551
2011 The α-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b). The Journal of biological chemistry 36 22194595
2002 Proapoptotic activity of ITM2B(s), a BH3-only protein induced upon IL-2-deprivation which interacts with Bcl-2. Oncogene 33 12082633
2018 The Bri2 and Bri3 BRICHOS Domains Interact Differently with Aβ42 and Alzheimer Amyloid Plaques. Journal of Alzheimer's disease reports 31 30480246
2001 Expression of BRI-amyloid beta peptide fusion proteins: a novel method for specific high-level expression of amyloid beta peptides. Biochimica et biophysica acta 31 11476963
2010 Bri2-23 is a potential cerebrospinal fluid biomarker in multiple sclerosis. Neurobiology of disease 29 20600910
2013 The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family. Human molecular genetics 26 24026677
2024 Body shape index (ABSI), body roundness index (BRI) and risk factors of metabolic syndrome among overweight and obese adults: a cross-sectional study. BMC endocrine disorders 24 39468529
2006 Molecular chaperons, amyloid and preamyloid lesions in the BRI2 gene-related dementias: a morphological study. Neuropathology and applied neurobiology 24 16972883
2014 Role of BRI2 in dementia. Journal of Alzheimer's disease : JAD 23 24473189
2008 Expression of BRI2 mRNA and protein in normal human brain and familial British dementia: its relevance to the pathogenesis of disease. Neuropathology and applied neurobiology 23 18282158
2019 The Familial dementia gene ITM2b/BRI2 facilitates glutamate transmission via both presynaptic and postsynaptic mechanisms. Scientific reports 22 30890756
2019 Interaction Between ITM2B and GLUT9 Links Urate Transport to Neurodegenerative Disorders. Frontiers in physiology 22 31695625
2013 Increased tau phosphorylation and tau truncation, and decreased synaptophysin levels in mutant BRI2/tau transgenic mice. PloS one 22 23418567
2017 Expression Pattern of the BCL6 and ITM2B Proteins in Normal Human Brains and in Alzheimer Disease. Applied immunohistochemistry & molecular morphology : AIMM 21 26862951
2008 BRI2 as a central protein involved in neurodegeneration. Biotechnology journal 21 19072909
2021 The role of the integral type II transmembrane protein BRI2 in health and disease. Cellular and molecular life sciences : CMLS 20 34480585
2019 Shaping of CD56bri Natural Killer Cells in Patients With Steroid-Refractory/Resistant Acute Graft-vs.-Host Disease via Extracorporeal Photopheresis. Frontiers in immunology 20 30949182
2013 BRI2 interacts with BACE1 and regulates its cellular levels by promoting its degradation and reducing its mRNA levels. Current Alzheimer research 19 23701002
2020 Danish and British dementia ITM2b/BRI2 mutations reduce BRI2 protein stability and impair glutamatergic synaptic transmission. The Journal of biological chemistry 18 33172889
2020 Functionalization of amyloid fibrils via the Bri2 BRICHOS domain. Scientific reports 17 33303867
1995 Uptake of Benzoic Acid and Chloro-Substituted Benzoic Acids by Alcaligenes denitrificans BRI 3010 and BRI 6011. Applied and environmental microbiology 17 16535175
2011 Glycosylation of BRI2 on asparagine 170 is involved in its trafficking to the cell surface but not in its processing by furin or ADAM10. Glycobiology 16 21752865
2008 BRI2 homodimerizes with the involvement of intermolecular disulfide bonds. Neurobiology of aging 16 18440095
2015 Accumulation of BRI2-BRICHOS ectodomain correlates with a decreased clearance of Aβ by insulin degrading enzyme (IDE) in Alzheimer's disease. Neuroscience letters 14 25597881
2000 Familial British dementia: expression and metabolism of BRI. Annals of the New York Academy of Sciences 14 11193182
2024 Ligand Homogenized Br-I Wide-Bandgap Perovskites for Efficient NiO-Based Inverted Semitransparent and Tandem Solar Cells. ACS nano 13 38829730
2021 A Novel ITM2B Mutation Associated with Familial Chinese Dementia. Journal of Alzheimer's disease : JAD 13 33814452
2017 BRI2 Processing and Its Neuritogenic Role Are Modulated by Protein Phosphatase 1 Complexing. Journal of cellular biochemistry 13 28176357
2015 Interaction of ApoE3 and ApoE4 isoforms with an ITM2b/BRI2 mutation linked to the Alzheimer disease-like Danish dementia: Effects on learning and memory. Neurobiology of learning and memory 13 26528887
2024 Functional BRI2-TREM2 interactions in microglia: implications for Alzheimer's and related dementias. EMBO reports 12 38347225
2021 Expression of the human molecular chaperone domain Bri2 BRICHOS on a gram per liter scale with an E. coli fed-batch culture. Microbial cell factories 12 34330289
2014 The ITM2B (BRI2) gene is a target of BCL6 repression: Implications for lymphomas and neurodegenerative diseases. Biochimica et biophysica acta 12 25557390
2019 A seminested RT-PCR for molecular genotyping of the Brazilian BR-I Infectious Bronchitis Virus Strain (GI-11). Molecular and cellular probes 11 31365883
2018 BRI2 as an anti-Alzheimer gene. Medical molecular morphology 11 29687167
2015 BRI2 and BRI3 are functionally distinct phosphoproteins. Cellular signalling 11 26515131
2014 BRI2 ectodomain affects Aβ42 fibrillation and tau truncation in human neuroblastoma cells. Cellular and molecular life sciences : CMLS 11 25336154
2011 Quality-of-life evaluation for advanced non-small-cell lung cancer: a comparison between vinorelbine plus gemcitabine followed by docetaxel versus paclitaxel plus carboplatin regimens in a randomized trial: Japan Multinational Trial Organization LC00-03 (BRI LC03-01). BMC cancer 11 21849041
2008 Enrichment of human beta 1 bri/alpha 6 bri/CD71 dim keratinocytes after culture in defined media. Cells, tissues, organs 11 18689990
2022 S100A9 amyloid growth and S100A9 fibril-induced impairment of gamma oscillations in area CA3 of mouse hippocampus ex vivo is prevented by Bri2 BRICHOS. Progress in neurobiology 9 36273719
2020 Brigatinib in ALK-positive non-small cell lung cancer: real-world data in the Latin American population (Bri-world extend CLICaP). Future oncology (London, England) 9 32986959
2004 Properties of neurotoxic peptides related to the Bri gene. Protein and peptide letters 9 15182222
2020 Analyses Mutations in GSN, CST3, TTR, and ITM2B Genes in Chinese Patients With Alzheimer's Disease. Frontiers in aging neuroscience 8 33192475
2016 Amyloid and intracellular accumulation of BRI2. Neurobiology of aging 8 28131015
2015 The Familial British Dementia Mutation Promotes Formation of Neurotoxic Cystine Cross-linked Amyloid Bri (ABri) Oligomers. The Journal of biological chemistry 8 25957407
2023 A Novel c.800G>C Variant of the ITM2B Gene in Familial Korean Dementia. Journal of Alzheimer's disease : JAD 7 37038821
2005 Structure and neurotoxicity of novel amyloids derived from the BRI gene. Biochemical Society transactions 7 16246057
2024 MicroRNA-196a-5p facilitates the onset and progression via targeting ITM2B in esophageal squamous cell carcinoma. Pathology international 6 38289121
2024 Specific inhibition of α-synuclein oligomer generation and toxicity by the chaperone domain Bri2 BRICHOS. Protein science : a publication of the Protein Society 6 38980078
2023 Antigenic and molecular characterization of isolates of the Brazilian genotype BR-I (GI-11) of infectious bronchitis virus supports its recognition as BR-I serotype. Avian pathology : journal of the W.V.P.A 6 37477586
2016 Gemcitabine treatment enhanced the anti-tumor effect of cytokine induced killer cells by depletion of CD4+CD25bri regulatory T cells. Immunology letters 6 27867030
2002 Properties of neurotoxic peptides related to the BRI gene. Biochemical Society transactions 6 12196136
2021 DEEP PHENOTYPING AND FURTHER INSIGHTS INTO ITM2B-RELATED RETINAL DYSTROPHY. Retina (Philadelphia, Pa.) 5 32826790
2025 CircRNA Itm2b induces oxidative stress via the interaction with Sirt1-Nox4 to aggravate sleep disturbances after traumatic brain injury. Cell & bioscience 4 39962534
2023 Identification of cytoskeletal proteins as binding partners of Bri2 BRICHOS domain. Molecular and cellular neurosciences 4 36935047
2023 The Brazilian Toxoplasma gondii strain BRI caused greater inflammation and impairment in anxiogenic behavior in mice, which was reverted by rosuvastatin treatment. Parasitology research 4 38117414
2021 Association of clusterin with the BRI2-derived amyloid molecules ABri and ADan. Neurobiology of disease 4 34298087
2019 Generation of human induced pluripotent stem cell lines from a patient with ITM2B-related retinal dystrophy and a non mutated brother. Stem cell research 4 31731182
2015 Metal ion mediated transition from random coil to β-sheet and aggregation of Bri2-23, a natural inhibitor of Aβ aggregation. Metallomics : integrated biometal science 4 25633876
2025 Determinants for Substoichiometric Inhibition of IAPP and Aβ Amyloid Aggregations by Bri2 BRICHOS. ACS chemical neuroscience 3 40035576
2025 Assessing Co-Localization of ITM2B With Alzheimer's Disease and Limbic-Predominant Age-Related TDP-43 Encephalopathy Neuropathologic Changes. Neuropathology : official journal of the Japanese Society of Neuropathology 2 40042444
2025 Massive mutagenesis reveals an incomplete amyloid motif in Bri2 that turns amyloidogenic upon C-terminal extension. Proceedings of the National Academy of Sciences of the United States of America 2 40314981
2025 Bri2 BRICHOS, a molecular chaperone-like domain that can cross brain vascular endothelial cells and deliver proteins into neurons. Journal of controlled release : official journal of the Controlled Release Society 2 41224179
2025 ITM2B Truncation Promotes Migrasome Formation to Accelerate Renal Cell Carcinoma Growth. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2 41319268
2024 Jmjd2c maintains the ALDHbri+ cancer stemness with transcription factor SOX2 in lung squamous cell carcinoma. Cancer biology & therapy 2 38975736
2024 CD56briCD38+ as a novel neutrophil-specific marker in chronic myeloid leukemia. Heliyon 2 39559206
2023 Generation of gene corrected human isogenic iPSC lines (IDVi003-A_CR13, IDVi003-A_CR21, IDVi003-A_CR24) from an inherited retinal dystrophy patient-derived IPSC line ITM2B-5286-3 (IDVi003-A) carrying the ITM2B c.782A > C variant using CRISPR/Cas9. Stem cell research 2 37473460
2022 Safety and efficacy of a feed additive consisting of endo-1,4-β-xylanase produced by Komagataella phaffiiDSM 33574, and viable spores of Bacillus velezensisDSM 21836 and Bacillus licheniformisATCC 53757 (EnzaPro) for chickens for fattening, chickens reared for laying/breeding, turkeys for fattening, turkeys reared for breeding and growing minor poultry species (BioResource International (BRI), Inc.). EFSA journal. European Food Safety Authority 2 36312450
2022 Imaging the Photodissociation Dynamics and Fragment Alignment of CH2BrI at 193 nm. The journal of physical chemistry. A 2 36322967
2021 The synthesis and characterization of Bri2 BRICHOS coated magnetic particles and their application to protein fishing: Identification of novel binding proteins. Journal of pharmaceutical and biomedical analysis 2 33690096
2024 Myelin Basic Protein Attenuates Furin-Mediated Bri2 Cleavage and Postpones Its Membrane Trafficking. International journal of molecular sciences 1 38473856
2023 BRI2-mediated regulation of TREM2 processing in microglia and its potential implications for Alzheimer's disease and related dementias. bioRxiv : the preprint server for biology 1 37398330

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