Affinage

HAX1

HCLS1-associated protein X-1 · UniProt O00165

Length
279 aa
Mass
31.6 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HAX1 is a multifunctional anti-apoptotic adaptor protein that integrates mitochondrial survival signaling, cytoskeletal regulation, and post-transcriptional mRNA control. At mitochondria, HAX1 preserves inner membrane potential by facilitating PARL-mediated processing of HtrA2, inhibiting caspase-9 processing, stabilizing XIAP against ubiquitin-dependent degradation, and promoting cyclophilin-D ubiquitination to suppress mitochondrial permeability transition pore opening (PMID:18288109, PMID:16857965, PMID:20171186, PMID:26553996). In cardiomyocytes, HAX1 forms a ternary complex with phospholamban (PLN) and SERCA2a, mediating approximately 50% of PLN's inhibitory effect on SERCA2a calcium affinity; its levels are controlled by FBXO25/PRKCD-dependent and βTrCP-dependent ubiquitination, counterbalanced by EIF3H deubiquitination, with stabilized HAX1 also scaffolding RAF1–MEK1–ERK1 signaling (PMID:29150445, PMID:25419709, PMID:38514606). Loss-of-function mutations cause autosomal recessive severe congenital neutropenia (Kostmann disease), with isoform-specific mutations additionally producing neurological deficits, and HAX1 deficiency impairs neutrophil differentiation through a CLPB/PRKD2/HSP27 proteostasis axis (PMID:17187068, PMID:18337561, PMID:35499078).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Identification of HAX-1 as a novel mitochondrial/ER-localized protein interacting with the Src-kinase substrate HS1 established its potential role as an intracellular adaptor linking kinase signaling to organelle function.

    Evidence Yeast two-hybrid, co-immunoprecipitation, confocal microscopy with deletion mapping in multiple cell lines

    PMID:9058808

    Open questions at the time
    • No function beyond binding was established
    • Endogenous interaction stoichiometry unknown
  2. 2002 Medium

    HAX-1 was shown to homodimerize and function as a potent apoptosis inhibitor, while also binding the 3′UTR of vimentin mRNA, revealing dual roles as both a survival factor and an RNA-binding protein.

    Evidence Apoptosis assays with overexpression, yeast three-hybrid RNA screen, in vitro RNA binding with recombinant protein

    PMID:11752170 PMID:12466525

    Open questions at the time
    • Physiological RNA targets not comprehensively mapped
    • Mechanism of anti-apoptotic activity undefined
  3. 2004 High

    Two mechanistic arms of HAX-1 function were established: Omi/HtrA2 cleaves HAX-1 as a pro-apoptotic mechanism within mitochondria, and HAX-1 mediates Gα13-stimulated cell migration by scaffolding a Gα13–Rac–cortactin complex while attenuating RhoA.

    Evidence In vitro cleavage with Omi inhibitors and catalytically inactive mutant; Co-IP of Gα13–HAX-1–cortactin with RhoA/Rac activity assays and siRNA migration phenotype

    PMID:15339924 PMID:15371414

    Open questions at the time
    • Omi cleavage site in HAX-1 not mapped
    • Relationship between cytoskeletal and mitochondrial functions not addressed
  4. 2006 High

    HAX1 was established as essential for human neutrophil survival—loss-of-function mutations cause Kostmann disease (severe congenital neutropenia)—while mechanistically HAX-1 was shown to inhibit caspase-9 processing and interact with the PLN–SERCA2a calcium-handling axis in cardiomyocytes.

    Evidence Positional cloning across multiple pedigrees with mitochondrial membrane potential assays; cell-free caspase-9 activation assay; SPR-measured PLN binding (Kd ~1 μM) with domain mapping

    PMID:16857965 PMID:17187068 PMID:17241641

    Open questions at the time
    • Whether neutropenia is purely apoptotic or also involves differentiation defects was unresolved
    • In vivo cardiac role not yet demonstrated
  5. 2008 High

    A mitochondrial anti-apoptotic pathway was delineated in which HAX-1 presents HtrA2 to the rhomboid protease PARL for processing, and isoform-genotype-phenotype correlations explained why some HAX1 mutations cause neurological disease in addition to neutropenia.

    Evidence Hax1 knockout mouse with biochemical mitochondrial processing assays; RT-PCR isoform expression mapping with clinical phenotyping across patients

    PMID:18288109 PMID:18337561

    Open questions at the time
    • PARL–HAX-1 interaction was subsequently challenged as a potential in vitro artifact (PMID:19680265)
    • Neuronal-specific functions of variant 2 remain mechanistically undefined
  6. 2010 High

    Granzyme B was shown to cleave HAX-1 within mitochondria generating a dominant-negative N-terminal fragment that triggers cyclophilin-D-dependent depolarization, while HAX-1 was found to stabilize XIAP by suppressing its polyubiquitination—defining two independent anti-apoptotic mechanisms.

    Evidence In vitro cleavage reconstitution with uncleavable mutant; SPR-confirmed XIAP binding with ubiquitination assay

    PMID:20171186 PMID:20388708

    Open questions at the time
    • Whether granzyme B cleavage of HAX-1 is rate-limiting for cytotoxic lymphocyte killing in vivo unknown
    • E3 ligase mediating XIAP ubiquitination antagonized by HAX-1 not identified
  7. 2012 High

    HAX-1 was shown to be a nucleocytoplasmic shuttling protein with CRM1-dependent nuclear export signals, co-localizing with P-bodies and influencing DNA polymerase β mRNA levels, while its own turnover is controlled by PEST-sequence-dependent K48-linked ubiquitination. Separately, HAX-1 was linked to G-CSF-stimulated HCLS1 phosphorylation and LEF-1 nuclear transport in granulopoiesis.

    Evidence Leptomycin B treatment with systematic NES mutagenesis; ubiquitination assays with PEST deletion mutants; patient cell studies with HCLS1-deficient mouse model

    PMID:22827267 PMID:23001182 PMID:23164465

    Open questions at the time
    • Full spectrum of HAX-1-regulated mRNAs not identified
    • Whether P-body localization is functionally required for mRNA surveillance unclear
  8. 2014 High

    The E3 ligase SCF(FBXO25) was identified as targeting HAX-1 for degradation after PRKCD-dependent phosphorylation during apoptotic stress, establishing the regulated degradation pathway whose dysregulation accelerates lymphomagenesis. HAX-1 was also shown to bridge Rac1–cortactin interaction for cell migration via defined binding domains.

    Evidence Unbiased substrate screen, phosphodegron mutants, mouse lymphoma model; domain mapping with competitive inhibitor peptides and migration assays

    PMID:25053987 PMID:25419709

    Open questions at the time
    • Whether FBXO25 is the sole E3 for HAX-1 degradation was unresolved (βTrCP later implicated)
    • Relative contributions of Rac vs RhoA arms in different cell types unclear
  9. 2015 High

    HAX-1 was found to regulate cyclophilin-D levels by disrupting its Hsp90-dependent stabilization, thereby controlling mPTP opening, and separately shown to interact with EB2 to regulate focal adhesion dynamics and epidermal migration.

    Evidence Cardiac overexpression/haploinsufficiency with cyclophilin-D KO epistasis; quantitative proteomics with in vivo migration validation

    PMID:26527684 PMID:26553996

    Open questions at the time
    • Whether cyclophilin-D regulation operates in non-cardiac tissues unknown
    • EB2–HAX-1 mechanism of focal adhesion destabilization not fully resolved
  10. 2016 High

    HAX-1 was established as an auxiliary subunit of Kv3.3 channels that recruits Arp2/3 to the plasma membrane to build cortical actin networks, preventing N-type inactivation; a human disease mutation in Kv3.3 binds HAX-1 but fails to recruit Arp2/3, linking HAX-1 to channelopathy.

    Evidence Co-immunoprecipitation, actin imaging, electrophysiology, stem cell-derived neurons with disease mutation

    PMID:26997484

    Open questions at the time
    • Structural basis of Kv3.3–HAX-1 interaction unresolved
    • Whether HAX-1 regulates other voltage-gated channels unknown
  11. 2017 High

    Inducible cardiac-specific HAX-1 ablation demonstrated that endogenous HAX-1 mediates ~50% of PLN's inhibitory effect on SERCA2a and protects SERCA2a from NOX4-dependent oxidative degradation, establishing HAX-1 as a central regulator of cardiac calcium cycling.

    Evidence Inducible cardiac-specific knockout with calcium kinetics, PLN-SERCA2a co-immunoprecipitation, ROS measurements, NOX4 co-immunoprecipitation

    PMID:29150445 PMID:29169992

    Open questions at the time
    • Whether HAX-1 regulation of SERCA2a is relevant in non-cardiac muscle or other tissues unknown
    • Precise stoichiometry of PLN–HAX-1–SERCA2a ternary complex not determined
  12. 2021 High

    The Kv3.3–HAX-1 pathway was extended upstream to TBK1, which is required for Kv3.3 binding to HAX-1; disease-causing Kv3.3 mutations overactivate TBK1, routing HAX-1 to lysosomes for degradation and triggering caspase-dependent cerebellar neuron death.

    Evidence Co-immunoprecipitation, TBK1 inhibition, MVB/lysosome trafficking, caspase and cell death assays

    PMID:33741962

    Open questions at the time
    • Whether TBK1 directly phosphorylates HAX-1 or acts indirectly is unknown
    • Relevance to non-Kv3.3-related neurodegenerative conditions not explored
  13. 2022 High

    SILAC proteomics revealed that HAX1 and CLPB co-regulate mitochondrial proteostasis, with HAX1 deficiency reducing PRKD2 abundance and HSP27 phosphorylation, impairing neutrophil differentiation—a defect rescued by HSP27 re-expression, establishing a non-apoptotic mechanism for Kostmann disease.

    Evidence SILAC proteomics in HAX1-knockout cells, HSP27 rescue experiments, phosphorylation assays

    PMID:35499078

    Open questions at the time
    • Whether the CLPB/HAX1/HSP27 axis is relevant to non-hematopoietic tissues unknown
    • Direct vs indirect regulation of PRKD2 by HAX1 not resolved
  14. 2024 High

    EIF3H was identified as a deubiquitinase that stabilizes HAX-1 by antagonizing βTrCP-mediated ubiquitination; stabilized HAX-1 scaffolds RAF1–MEK1–ERK1 interactions to potentiate MAPK signaling and promote colorectal cancer progression, revealing HAX-1 as a signaling scaffold beyond its anti-apoptotic role.

    Evidence Deubiquitinase assay, Co-IP of RAF1–MEK1–ERK1, ubiquitination assays, mouse orthotopic cancer model

    PMID:38514606

    Open questions at the time
    • Whether HAX-1's MAPK scaffolding function operates in normal physiology or only in cancer context unknown
    • βTrCP degron site on HAX-1 not precisely mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • No high-resolution structure of HAX-1 exists, and the structural basis for its multivalent interactions with diverse partners (PLN, SERCA2a, cortactin, Rac1, Kv3.3, caspase-9, XIAP, RAF1) remains undefined. The relative importance of HAX-1's anti-apoptotic versus cytoskeletal versus mRNA regulatory functions in neutrophil biology and disease pathogenesis is incompletely resolved.
  • No crystal or cryo-EM structure available
  • Comprehensive interactome under physiological conditions not established
  • Cell-type-specific functions of individual HAX-1 isoforms remain poorly characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0003723 RNA binding 2
Localization
GO:0005739 mitochondrion 5 GO:0005783 endoplasmic reticulum 3 GO:0005634 nucleus 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-5357801 Programmed Cell Death 6 R-HSA-168256 Immune System 3 R-HSA-382551 Transport of small molecules 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-162582 Signal Transduction 2
Partners
ATP2A2CASP9EIF3HFBXO25HCLS1KCNC3PLNXIAP
Complex memberships
Gα13-HAX1-Rac1-cortactinKv3.3-TBK1-HAX1-Arp2/3PLN-HAX1-SERCA2a

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 HAX-1 was identified as a novel intracellular protein that directly associates with HS1 (a substrate of Src family tyrosine kinases); the association is mediated by the amino-terminal region of HS1 and the carboxyl-terminal half of HAX-1, confirmed by yeast two-hybrid, co-immunoprecipitation, and confocal colocalization. HAX-1 localizes mainly to mitochondria but also to endoplasmic reticulum and nuclear envelope. Yeast two-hybrid screening, co-immunoprecipitation, confocal microscopy, deletion mutant analysis Journal of Immunology High 9058808
2000 HAX-1 interacts with the polycystic kidney disease protein PKD2 (but not the closely related PKD2L), and associates with the F-actin-binding protein cortactin, linking PKD2 to the actin cytoskeleton. PKD2 and HAX-1 co-localize in cellular processes and lamellipodia. Yeast two-hybrid screen, immunofluorescence co-localization PNAS Medium 10760273
2002 HAX-1 can form homodimers in vivo and functions as a potent inhibitor of apoptosis. The KSHV K15 protein interacts with HAX-1 in vitro and in vivo, and HAX-1 co-localizes with K15 in the endoplasmic reticulum and mitochondria. Yeast two-hybrid, in vitro binding, co-immunoprecipitation, immunofluorescence, apoptosis assays Journal of Virology Medium 11752170
2002 HAX-1 binds the 3' untranslated region of vimentin mRNA as part of protein complexes also containing eEF-1gamma; recombinant HAX-1 protein binds this RNA in vitro with apparent specificity for vimentin's 3'UTR, identifying HAX-1 as an RNA-binding protein potentially involved in mRNA localization or stability. Yeast three-hybrid, RNA affinity pull-down from HeLa extracts, in vitro RNA-binding assay Nucleic Acids Research Medium 12466525
2004 Omi/HtrA2 serine protease cleaves HAX-1 both in vitro and in vivo; HAX-1 degradation occurs early in apoptosis while Omi is still mitochondria-confined, suggesting Omi has a pro-apoptotic function within mitochondria by removing the anti-apoptotic HAX-1 protein. Cleavage is prevented by Omi-specific inhibitors and absent in cells with proteolytically inactive Omi. In vitro cleavage assay, cell-based apoptosis induction with specific Omi inhibitors, cell line with mutant Omi Journal of Biological Chemistry High 15371414
2004 HAX-1 was identified as a binding partner of BSEP, MDR1, and MDR2 ABC transporters; HAX-1 depletion by RNAi increased BSEP levels in the apical membrane of MDCK cells by 71% by enhancing retention without affecting translation or post-translational modification, suggesting HAX-1 participates in internalization of BSEP from the apical membrane. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, RNAi, pulse-chase Journal of Biological Chemistry High 15159385
2004 Gα13 physically interacts with HAX-1 (a cortactin-interacting protein); this interaction is required for Gα13-stimulated cell migration. HAX-1 expression reduces actin stress fibers and focal adhesion complexes, attenuates Gα13-stimulated RhoA activity while potentiating Rac activity, and participates in a quaternary complex with Gα13, Rac, and cortactin. HAX-1 siRNA knockdown drastically reduces Gα13-mediated cell migration. Co-immunoprecipitation, RhoA/Rac activity assays, siRNA knockdown, cell migration assays Journal of Biological Chemistry High 15339924
2005 HIV-1 Vpr physically associates with HAX-1; overexpression of Vpr dislocates HAX-1 from its normal mitochondrial residence, causing mitochondrial instability and cell death. Conversely, HAX-1 overexpression suppresses Vpr's pro-apoptotic activity. Co-immunoprecipitation, immunofluorescence localization, overexpression/rescue experiments Journal of Virology Medium 16227293
2006 HAX-1 is critical for maintaining the inner mitochondrial membrane potential and protecting against apoptosis in myeloid cells; loss-of-function HAX1 mutations cause autosomal recessive severe congenital neutropenia (Kostmann disease) with increased apoptosis in myeloid cells. Positional cloning, mitochondrial membrane potential assays in patient cells Nature Genetics High 17187068
2006 HAX-1 interacts with caspase-9 through yeast two-hybrid; recombinant HAX-1 inhibits caspase-9 processing in a dose-dependent manner in a cell-free caspase activation assay. HAX-1 overexpression protects adult cardiac myocytes from apoptosis; HAX-1 siRNA knockdown causes significant cell death. On apoptotic stimulation, caspase-9 translocates to mitochondria and co-localizes with HAX-1. Yeast two-hybrid, cell-free caspase activation assay, siRNA knockdown, immunofluorescence Circulation Research High 16857965
2006 HAX-1 interacts with phospholamban (PLN); minimal binding regions mapped to amino acids 203-245 of HAX-1 and residues 16-22 of PLN, confirmed by GST pull-down and surface plasmon resonance (Kd ~1 µM). Phosphorylation of PLN by PKA reduced HAX-1 binding; elevated Ca2+ diminished the interaction. Upon PLN co-expression, HAX-1 redistributes from mitochondria to ER, and PLN enhances HAX-1's anti-apoptotic protection from hypoxia/reoxygenation. Yeast two-hybrid, GST pull-down, surface plasmon resonance, subcellular localization by transfection, apoptosis assay Journal of Molecular Biology High 17241641
2007 HAX-1 binds to a hairpin structure in the 3'UTR of DNA polymerase beta mRNA in vitro; this interaction requires the intact hairpin motif. HAX-1 binds as a dimer; HAX-1 is present in nuclear matrix fractions in addition to mitochondria, suggesting a role in post-transcriptional regulation. RNA-protein binding assay (gel shift, UV-crosslinking), luciferase reporter system, biochemical fractionation, dimerization analysis Nucleic Acids Research Medium 17704138
2008 HAX-1 is required for Parl-mediated processing of HtrA2 to its active form in mitochondria: Hax1 interacts with both the mitochondrial rhomboid protease Parl and HtrA2, presenting HtrA2 to Parl for proteolytic processing. Processed HtrA2 in the intermembrane space prevents accumulation of activated Bax at the outer mitochondrial membrane. Loss of Hax1 in mouse lymphocytes and neurons leads to increased apoptosis. Genetic mouse knockout, biochemical interaction studies, mitochondrial processing assays Nature High 18288109
2008 HAX-1 isoforms show genotype-phenotype correlation in congenital neutropenia: mutations affecting only transcript variant 1 cause neutropenia alone, while mutations affecting both transcript variants cause neutropenia plus neurological symptoms (epilepsy, developmental delay), reflecting differential expression of variant 2 in brain tissue. Molecular screening, RT-PCR of isoform expression in tissues, clinical phenotype analysis Blood Medium 18337561
2008 HAX-1 binds to SERCA2 at amino acid residues 575-594 of SERCA2's nucleotide binding domain, interacting with the C-terminal domain (aa 203-245) of HAX-1. Triple transfection with PLN causes massive HAX-1 redistribution from mitochondria to ER where it co-distributes with PLN and SERCA2. SERCA2 overexpression abolishes HAX-1's protective effects on cell survival; HAX-1 overexpression down-regulates SERCA2 protein levels and reduces ER Ca2+ stores. Co-immunoprecipitation, deletion mapping, subcellular localization by transfection, cell survival assay, Ca2+ measurements Molecular Biology of the Cell High 18971376
2008 HAX-1 interacts with HIV-1 Rev and inhibits Rev/RRE-mediated gene expression by preventing Rev from binding to RRE RNA in vitro, and by relocating Rev from the nucleus to the cytoplasm when co-expressed. Co-immunoprecipitation, in vitro RNA binding assay, immunofluorescence, reporter gene assay Journal of Cellular Physiology Medium 17929250
2009 HAX-1 overexpression reduces SERCA2 pump activity in cardiomyocytes and in vivo, depressing calcium kinetics and contractility. HAX-1 promotes formation of phospholamban monomers (the active/inhibitory units of the Ca pump). The inhibitory effects of HAX-1 are abolished upon PLN phosphorylation, and PLN ablation rescues HAX-1 inhibition of contractility in vivo. Transgenic mouse overexpression, cardiomyocyte Ca2+ measurements, contractility assays, PLN ablation genetic epistasis PNAS High 19920172
2009 Hax-1 lacks bona fide Bcl-2 homology modules based on sequence analysis and secondary structure prediction, and in vivo the two proteins (Hax1 and PARL) are confined to distinct cellular compartments; their reported interaction is concluded to be an in vitro artifact, challenging the Hax1-PARL mechanistic model. Sequence/structure analysis, subcellular fractionation, in vitro interaction control experiments Cell Death and Differentiation Medium 19680265
2010 Granzyme B inserts into a proteinase K-resistant mitochondrial compartment and cleaves Hax-1 into an N-terminal fragment (retained at mitochondria) and a C-terminal fragment (released to cytosol). The N-terminal Hax-1 fragment acts as a dominant negative, mediating mitochondrial depolarization in a cyclophilin-D-dependent manner. Overexpression of wild-type or uncleavable mutant Hax-1 protects mitochondria from GrB-mediated depolarization. In vitro cleavage assay, mitochondrial import/fractionation, uncleavable mutant overexpression, mitochondrial membrane potential assay Journal of Biological Chemistry High 20388708
2010 HAX-1 interacts with XIAP at its BIR2 and BIR3 domains, while XIAP binds the C-terminal domain of HAX-1; HAX-1 suppresses polyubiquitination of XIAP, stabilizing it against proteasomal degradation, thereby inhibiting apoptosis. Immunoprecipitation, 2D gel electrophoresis proteomics, GST pull-down, surface plasmon resonance, ubiquitination assay Biochemical and Biophysical Research Communications High 20171186
2011 Hax1 is a negative regulator of integrin-mediated adhesion and chemotaxis in neutrophils: Hax1 depletion impairs uropod detachment and directed migration, increases integrin-mediated adhesion, and reduces RhoA activity. RhoA depletion phenocopies Hax1 loss; RhoA activation rescues adhesion of Hax1-deficient neutrophils, placing Hax1 upstream of RhoA in the regulation of neutrophil migration. RNAi knockdown in PLB-985 cells, microfluidics, RhoA activity assays, rescue by constitutively active RhoA Journal of Cell Biology High 21518791
2012 HAX-1 interacts with the influenza A virus PA polymerase subunit (specifically at PA's nuclear localization signal domain) and impedes PA nuclear translocation; HAX-1 knockdown increases nuclear PA accumulation and viral polymerase activity, whereas reexpression of HAX-1 reverses this, defining HAX-1 as a host restriction factor for influenza A. GST pull-down, co-immunoprecipitation, nuclear/cytoplasmic fractionation, HAX-1 knockdown and rescue, viral polymerase minigenome assay Journal of Virology High 23055567
2012 HAX1 is required for G-CSF-triggered phosphorylation of HCLS1/HS1, which transports LEF-1 into the nucleus upon G-CSF stimulation; HAX1 mutations in congenital neutropenia patients cause defective HCLS1 phosphorylation and reduced LEF-1 autoregulation, impairing granulopoiesis. Phosphorylation assays, nuclear transport assays, patient cell studies, HCLS1-deficient mouse model Nature Medicine High 23001182
2012 HAX-1 is a nucleocytoplasmic shuttling protein dependent on exportin-1 (XPO1/CRM1) for nuclear export; two nuclear export signals were identified by systematic mutagenesis. HAX-1 nuclear accumulation occurs after leptomycin B treatment or specific cellular stress. HAX-1 co-localizes with P-body markers and its status influences DNA polymerase β mRNA levels. Leptomycin B treatment, systematic mutagenesis of NES sequences, immunofluorescence, P-body co-localization FEBS Journal High 23164465
2012 Hax-1 is rapidly degraded by the proteasome via K48-linked ubiquitin chains dependent on its PEST sequence; a deletion mutant lacking the PEST sequence is more resistant to proteasomal degradation and provides greater protection against apoptosis than wild-type Hax-1. Ubiquitination assay, proteasome inhibitor treatment, deletion mutagenesis, apoptosis assay BMC Cell Biology High 22827267
2012 HAX-1 overexpression improves contractile recovery after cardiac ischemia/reperfusion and inhibits the IRE-1 ER stress signaling pathway (including caspase-12 and CHOP) through its binding to the N-terminal fragment of Hsp90; HAX-1 sequesters Hsp90 from IRE-1 to the PLN-SERCA complex. Cardiac-specific transgenic overexpression, Hsp90 co-immunoprecipitation, IRE-1 activity assays, Hsp90 inhibitor pharmacology Circulation Research High 22982986
2013 Hax-1 proteins form homotypic and heterotypic dimers; variant 1 is anti-apoptotic while variant 2 (rat) / variant 4 (human) is pro-apoptotic. Co-expression of v1 and v2 neutralizes both activities by modulating cytochrome c release. Dimerization affinities range from ~3.8 nM for v1 homodimers to ~97 nM for v1/v2 heterodimers; minimal binding region spans aa 97-278. Surface plasmon resonance, cytochrome c release assay, overexpression of individual isoforms, deletion mapping Journal of Biological Chemistry High 24347163
2013 Hax-1 was identified as a binding partner of two-pore channels TPC1 and TPC2 using yeast two-hybrid screen, with biochemical confirmation; the interaction may represent a mechanism by which endolysosomal ion channels are regulated. Yeast two-hybrid, biochemical validation (pulldown/Co-IP) FEBS Letters Low 24188827
2014 FBXO25 is the substrate-recognition subunit of SCF(FBXO25) ubiquitin ligase that targets HAX-1 for proteasomal degradation after apoptotic stress; PRKCD initiates this by phosphorylating both FBXO25 and HAX-1, directing nuclear FBXO25 to mitochondrial HAX-1. HAX-1 phosphodegron mutations prevent degradation and inhibit apoptosis; FBXO25 loss accelerates lymphomagenesis. Unbiased substrate screen, co-immunoprecipitation, ubiquitination assay, phosphorylation assay, mouse lymphoma model, xenotransplant Nature Medicine High 25419709
2014 Hax-1 is required for Rac1-cortactin interaction in ovarian cancer cell migration; Hax-1 interacts with cortactin via domains aa 1-56 and aa 113-168, and with Rac1 via domains aa 57-112 and aa 169-224. Expression of competitive inhibitor domains reduces Rac1-cortactin colocalization and LPA-stimulated migration. Co-immunoprecipitation, domain mapping, siRNA knockdown, competitive inhibitor domain expression, migration assays Genes & Cancer Medium 25053987
2015 HAX-1 regulates cyclophilin-D protein levels and mitochondrial permeability transition pore (mPTP) activation: HAX-1 overexpression promotes cyclophilin-D ubiquitination and proteasomal degradation by interfering with cyclophilin-D binding to Hsp90 in mitochondria, thereby protecting against mPTP-mediated cell death. Cardiac-specific overexpression/heterozygous deficiency models, ubiquitination assay, proteasome inhibitor treatment, cyclophilin-D KO genetic epistasis, Hsp90 co-immunoprecipitation PNAS High 26553996
2015 HAX-1 interacts with EB2 (microtubule end-binding protein 2) as identified by quantitative proteomics; knockdown of either HAX1 or EB2 stabilizes focal adhesions and impairs epidermal cell migration in vitro and in vivo, and this motility requires their interaction. Quantitative proteomics, co-immunoprecipitation, RNAi knockdown, in vitro and in vivo migration assays Journal of Biological Chemistry High 26527684
2016 Kv3.3 channels recruit Arp2/3 to the plasma membrane via binding of Kv3.3's cytoplasmic C terminus to Hax-1, forming a cortical actin network resistant to cytochalasin D. These actin structures prevent rapid N-type channel inactivation. A human Kv3.3 disease mutation binds Hax-1 but cannot recruit Arp2/3, resulting in deficient actin veils in neurons. Co-immunoprecipitation, actin imaging, cytochalasin D treatment, electrophysiology, stem cell-derived neurons with disease mutation Cell High 26997484
2017 HAX-1 regulates SERCA2a oxidation and degradation through two mechanisms: (1) binding to NAPDH oxidase 4 (NOX4) to reduce ROS production at the SR compartment, thereby reducing SERCA2a oxidation and proteolysis; (2) HAX-1 ablation increases NOX4-dependent ROS. Inducible cardiac-specific HAX-1 knockout impairs contractile recovery and increases infarct size after ischemia/reperfusion. Inducible cardiac-specific knockout, ROS measurements, SR microsome fractionation, NOX4 co-immunoprecipitation, apocynin pharmacology Journal of Molecular and Cellular Cardiology High 29169992
2017 Endogenous HAX-1 mediates approximately 50% of PLN's inhibitory activity on SERCA2a in the heart; cardiac-specific inducible HAX-1 ablation increases calcium affinity of SERCA2a and reduces PLN-SERCA2a binding without changing protein expression levels of SERCA2a, PLN, or ryanodine receptor. Inducible cardiac-specific knockout, calcium kinetics measurements, PLN-SERCA2a co-immunoprecipitation, isoproterenol stimulation, PLN-null genetic comparison Journal of Biological Chemistry High 29150445
2019 HAX-1 collectively regulates actomyosin contractility through RhoA and septin signaling: HAX-1 knockdown affects cell-cell junctions, substrate adhesion, and epithelial layer integrity. HAX-1 impacts collective but not single-cell migration. HAX-1 siRNA knockdown, RhoA activity assays, adhesion assays, collective migration assay Molecular Biology of the Cell Medium 31644363
2020 HAX-1 interacts with inositol 1,4,5-trisphosphate receptor-1 (InsP3R1) in the liver; hepatic HAX-1 ablation reduces InsP3R1 levels, improving ER-mitochondria calcium homeostasis, activating pyruvate dehydrogenase, and increasing mitochondrial utilization of glucose and fatty acids. HAX-1 ablation also increases bile salt exporter protein (BSEP) levels to promote enterohepatic bile acid recirculation. Liver-specific knockout, InsP3R1 co-immunoprecipitation, mitochondrial respiration assays, calcium homeostasis measurements Journal of Biological Chemistry High 32079675
2021 Kv3.3 channels bind and stimulate TBK1 (TANK-binding kinase 1); TBK1 activity is required for Kv3.3 to bind its auxiliary subunit Hax-1, which prevents channel inactivation. Disease-causing Kv3.3 mutation overactivates TBK1, leading to Hax-1 accumulation in multivesicular bodies/lysosomes, loss of Hax-1, caspase activation, and cerebellar neuron death. Co-immunoprecipitation, TBK1 inhibition, MVB/lysosome trafficking assay, caspase activation, cell death assay Nature Communications High 33741962
2022 HAX1 and CLPB control the balance of mitochondrial protein synthesis and persistence (mitochondrial proteostasis), as shown by SILAC proteomics. HAX1/CLPB deficiency decreases PRKD2 abundance and phosphorylation of HSP27 on serines 78 and 82, impairing neutrophil granulocyte differentiation. Cellular defects in HAX1-/- cells can be rescued by HSP27, defining a CLPB/HAX1/(PRKD2)/HSP27 axis. SILAC proteomics, genetic knockout, HSP27 rescue experiments, HSP27 phosphorylation assays Journal of Clinical Investigation High 35499078
2024 EIF3H functions as a deubiquitinase for HAX-1, stabilizing it by antagonizing βTrCP-mediated ubiquitination; stabilized HAX-1 enhances the interaction between RAF1, MEK1, and ERK1, potentiating ERK1/2 phosphorylation and promoting colorectal cancer progression. Co-immunoprecipitation, ubiquitination assay, deubiquitinase assay, RAF1-MEK1-ERK1 interaction mapping, mouse orthotopic cancer model Nature Communications High 38514606

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nature genetics 363 17187068
2008 Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature 217 18288109
1997 HAX-1, a novel intracellular protein, localized on mitochondria, directly associates with HS1, a substrate of Src family tyrosine kinases. Journal of immunology (Baltimore, Md. : 1950) 215 9058808
2002 K15 protein of Kaposi's sarcoma-associated herpesvirus is latently expressed and binds to HAX-1, a protein with antiapoptotic function. Journal of virology 164 11752170
2000 The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton. Proceedings of the National Academy of Sciences of the United States of America 160 10760273
2004 Regulation of HAX-1 anti-apoptotic protein by Omi/HtrA2 protease during cell death. The Journal of biological chemistry 152 15371414
2009 Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. British journal of haematology 129 19775295
2004 Galpha13 stimulates cell migration through cortactin-interacting protein Hax-1. The Journal of biological chemistry 122 15339924
2006 Overexpression of HAX-1 protects cardiac myocytes from apoptosis through caspase-9 inhibition. Circulation research 121 16857965
2008 Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia. British journal of haematology 101 19120359
2009 HAX-1: a multifunctional protein with emerging roles in human disease. Biochimica et biophysica acta 99 19524642
2008 The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival. Molecular biology of the cell 92 18971376
2004 Identification of HAX-1 as a protein that binds bile salt export protein and regulates its abundance in the apical membrane of Madin-Darby canine kidney cells. The Journal of biological chemistry 92 15159385
2008 Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype-phenotype associations. Blood 91 18337561
2006 Phospholamban interacts with HAX-1, a mitochondrial protein with anti-apoptotic function. Journal of molecular biology 88 17241641
2012 Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis. Nature medicine 72 23001182
2008 Central nervous system involvement in severe congenital neutropenia: neurological and neuropsychological abnormalities associated with specific HAX1 mutations. Journal of internal medicine 70 18513342
2005 Human immunodeficiency virus type 1 Vpr interacts with antiapoptotic mitochondrial protein HAX-1. Journal of virology 69 16227293
2002 The 3' untranslated region of human vimentin mRNA interacts with protein complexes containing eEF-1gamma and HAX-1. Nucleic acids research 69 12466525
2016 MicroRNA-223 Increases the Sensitivity of Triple-Negative Breast Cancer Stem Cells to TRAIL-Induced Apoptosis by Targeting HAX-1. PloS one 68 27618431
2012 Novel role of HAX-1 in ischemic injury protection involvement of heat shock protein 90. Circulation research 68 22982986
2015 HAX-1 regulates cyclophilin-D levels and mitochondria permeability transition pore in the heart. Proceedings of the National Academy of Sciences of the United States of America 65 26553996
2016 Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating. Cell 60 26997484
2010 HAX-1 overexpression, splicing and cellular localization in tumors. BMC cancer 60 20196840
2014 Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis. Nature medicine 53 25419709
2009 The anti-apoptotic protein HAX-1 is a regulator of cardiac function. Proceedings of the National Academy of Sciences of the United States of America 51 19920172
2013 Genetic correction of HAX1 in induced pluripotent stem cells from a patient with severe congenital neutropenia improves defective granulopoiesis. Haematologica 48 23975175
2012 Cellular protein HAX1 interacts with the influenza A virus PA polymerase subunit and impedes its nuclear translocation. Journal of virology 47 23055567
2001 Epstein-Barr virus nuclear antigen 5 interacts with HAX-1, a possible component of the B-cell receptor signalling pathway. The Journal of general virology 47 11413368
2008 Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene. Journal of medical genetics 46 18611981
2003 HAX-1, identified by differential display reverse transcription polymerase chain reaction, is overexpressed in lesional psoriasis. The Journal of investigative dermatology 46 12787133
2011 HAX-1: a family of apoptotic regulators in health and disease. Journal of cellular physiology 45 21302289
2016 Inhibition of HAX-1 by miR-125a reverses cisplatin resistance in laryngeal cancer stem cells. Oncotarget 44 27880721
2016 Clinical and biological significance of HAX-1 overexpression in nasopharyngeal carcinoma. Oncotarget 43 26871467
2011 Hax1 regulates neutrophil adhesion and motility through RhoA. The Journal of cell biology 43 21518791
2009 Hax1 lacks BH modules and is peripherally associated to heavy membranes: implications for Omi/HtrA2 and PARL activity in the regulation of mitochondrial stress and apoptosis. Cell death and differentiation 42 19680265
2007 Hairpin structure within the 3'UTR of DNA polymerase beta mRNA acts as a post-transcriptional regulatory element and interacts with Hax-1. Nucleic acids research 42 17704138
2017 miR-125b regulates the drug-resistance of breast cancer cells to doxorubicin by targeting HAX-1. Oncology letters 40 29434858
2010 Molecular interaction between HAX-1 and XIAP inhibits apoptosis. Biochemical and biophysical research communications 38 20171186
2010 Deregulation of mitochondrial membrane potential by mitochondrial insertion of granzyme B and direct Hax-1 cleavage. The Journal of biological chemistry 38 20388708
2022 Extracellular vesicles rich in HAX1 promote angiogenesis by modulating ITGB6 translation. Journal of extracellular vesicles 37 35524442
2001 Evidence that HAX-1 is an interleukin-1 alpha N-terminal binding protein. Cytokine 37 11554782
2022 HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation. The Journal of clinical investigation 36 35499078
2011 Hax-1: a regulator of calcium signaling and apoptosis progression with multiple roles in human disease. Expert opinion on therapeutic targets 35 21391832
2012 HAX-1 is a nucleocytoplasmic shuttling protein with a possible role in mRNA processing. The FEBS journal 34 23164465
2015 HAX-1 inhibits apoptosis in prostate cancer through the suppression of caspase-9 activation. Oncology reports 31 26323553
2018 miR-100 Reverses Cisplatin Resistance in Breast Cancer by Suppressing HAX-1. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 30 29975932
2015 Protease Omi cleaving Hax-1 protein contributes to OGD/R-induced mitochondrial damage in neuroblastoma N2a cells and cerebral injury in MCAO mice. Acta pharmacologica Sinica 30 26299953
2016 Kostmann's Disease and HCLS1-Associated Protein X-1 (HAX1). Journal of clinical immunology 29 27943080
2009 Hepatitis C virus core protein and cellular protein HAX-1 promote 5-fluorouracil-mediated hepatocyte growth inhibition. Journal of virology 29 19605487
2007 Association of HAX1 deficiency with neurological disorder. Neuropediatrics 29 18330843
2012 Hax-1 is rapidly degraded by the proteasome dependent on its PEST sequence. BMC cell biology 28 22827267
2010 The classical swine fever virus N-terminal protease N(pro) binds to cellular HAX-1. The Journal of general virology 28 20631090
2009 Neutrophil elastase is severely down-regulated in severe congenital neutropenia independent of ELA2 or HAX1 mutations but dependent on LEF-1. Blood 28 19620402
2006 Identification and expression analysis of alternative splice variants of the rat Hax-1 gene. Gene 27 16516414
2019 Upregulation of let-7f-2-3p by long noncoding RNA NEAT1 inhibits XPO1-mediated HAX-1 nuclear export in both in vitro and in vivo rodent models of doxorubicin-induced cardiotoxicity. Archives of toxicology 26 31570982
2015 Regulation of Focal Adhesion Dynamics and Cell Motility by the EB2 and Hax1 Protein Complex. The Journal of biological chemistry 26 26527684
2009 HAX-1: a multifaceted antiapoptotic protein localizing in the mitochondria and the sarcoplasmic reticulum of striated muscle cells. Journal of molecular and cellular cardiology 26 19913549
2008 An anti-apoptotic protein, Hax-1, inhibits the HIV-1 rev function by altering its sub-cellular localization. Journal of cellular physiology 26 17929250
2007 Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency. Haematologica 26 18055975
2017 HAX-1 regulates SERCA2a oxidation and degradation. Journal of molecular and cellular cardiology 25 29169992
2016 KDM4B plays an important role in mitochondrial apoptosis by upregulating HAX1 expression in colorectal cancer. Oncotarget 25 27506941
2010 HAX1 mutations causing severe congenital neuropenia and neurological disease lead to cerebral microstructural abnormalities documented by quantitative MRI. American journal of medical genetics. Part A 25 21108402
2024 The EIF3H-HAX1 axis increases RAF-MEK-ERK signaling activity to promote colorectal cancer progression. Nature communications 24 38514606
2019 HAX-1 promotes the migration and invasion of hepatocellular carcinoma cells through the induction of epithelial-mesenchymal transition via the NF-κB pathway. Experimental cell research 24 31047882
2010 Pelota interacts with HAX1, EIF3G and SRPX and the resulting protein complexes are associated with the actin cytoskeleton. BMC cell biology 24 20406461
2009 Induction of apoptosis by Hax-1 siRNA in melanoma cells. Cell biology international 24 19254774
2015 Expression of HAX-1 in colorectal cancer and its role in cancer cell growth. Molecular medicine reports 23 26062578
2011 hSav1 interacts with HAX1 and attenuates its anti-apoptotic effects in MCF-7 breast cancer cells. International journal of molecular medicine 23 21567072
2021 Cerebellar Kv3.3 potassium channels activate TANK-binding kinase 1 to regulate trafficking of the cell survival protein Hax-1. Nature communications 22 33741962
2016 Endoplasmic reticulum (ER) stress triggers Hax1-dependent mitochondrial apoptotic events in cardiac cells. Apoptosis : an international journal on programmed cell death 22 27654581
2012 HAX-1 promotes the chemoresistance, invasion, and tumorigenicity of esophageal squamous carcinoma cells. Digestive diseases and sciences 22 22451114
2018 H5N1 Influenza A Virus PB1-F2 Relieves HAX-1-Mediated Restriction of Avian Virus Polymerase PA in Human Lung Cells. Journal of virology 21 29563290
2013 Competition through dimerization between antiapoptotic and proapoptotic HS-1-associated protein X-1 (Hax-1). The Journal of biological chemistry 21 24347163
2006 Expression and tissue distribution of mouse Hax1. Gene 21 16814492
2019 Homozygous c.130-131 ins A (pW44X) mutation in the HAX1 gene as the most common cause of congenital neutropenia in Turkey: Report from the Turkish Severe Congenital Neutropenia Registry. Pediatric blood & cancer 20 31321910
2014 Neurological findings and genetic alterations in patients with Kostmann syndrome and HAX1 mutations. Pediatric blood & cancer 20 24482108
2014 Hax-1 is required for Rac1-Cortactin interaction and ovarian carcinoma cell migration. Genes & cancer 20 25053987
2013 Expression of HAX-1 in human colorectal cancer and its clinical significance. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 20 24057929
2013 Hax-1 identified as a two-pore channel (TPC)-binding protein. FEBS letters 20 24188827
2010 HAX1 deficiency: impact on lymphopoiesis and B-cell development. European journal of immunology 20 20865787
2008 Homozygous HAX1 mutations in severe congenital neutropenia patients with sporadic disease: a novel mutation in two unrelated British kindreds. British journal of haematology 20 19036076
2017 The antiapoptotic protein HAX-1 mediates half of phospholamban's inhibitory activity on calcium cycling and contractility in the heart. The Journal of biological chemistry 19 29150445
2017 Gene correction of HAX1 reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells. Blood advances 19 29296734
2017 HAX-1 Protects Glioblastoma Cells from Apoptosis through the Akt1 Pathway. Frontiers in cellular neuroscience 19 29311840
2015 HAX-1 is overexpressed in hepatocellular carcinoma and promotes cell proliferation. International journal of clinical and experimental pathology 18 26339377
2020 HAX1 enhances the survival and metastasis of non-small cell lung cancer through the AKT/mTOR and MDM2/p53 signaling pathway. Thoracic cancer 16 32926529
2018 Critical Role of HAX-1 in Promoting Avian Influenza Virus Replication in Lung Epithelial Cells. Mediators of inflammation 16 29576744
2008 Necrosis of nasal cartilage due to mucormycosis in a patient with severe congenital neutropenia due to HAX1 deficiency. Journal of investigational allergology & clinical immunology 16 19123440
2020 Hepatic HAX-1 inactivation prevents metabolic diseases by enhancing mitochondrial activity and bile salt export. The Journal of biological chemistry 15 32079675
2020 miR-654-5p Targets HAX-1 to Regulate the Malignancy Behaviors of Colorectal Cancer Cells. BioMed research international 15 32104694
2014 Exploring the anti-apoptotic role of HAX-1 versus BCL-XL in cytokine-dependent bone marrow-derived cells from mice. FEBS letters 15 24910348
2010 A novel HAX1 gene mutation in severe congenital neutropenia (SCN) associated with neurological manifestations. European journal of pediatrics 15 20182745
2019 HAX1 impact on collective cell migration, cell adhesion, and cell shape is linked to the regulation of actomyosin contractility. Molecular biology of the cell 14 31644363
2014 Clinical significance of HAX-1 expression in laryngeal carcinoma. Auris, nasus, larynx 14 25554539
2012 HAX1 Augments Cell Proliferation, Migration, Adhesion, and Invasion Induced by Urokinase-Type Plasminogen Activator Receptor. Journal of oncology 14 22315598
2010 Traumatic brain injury induces an up-regulation of Hs1-associated protein X-1 (Hax-1) in rat brain cortex. Neurochemical research 14 21136158
2021 A zebrafish model for HAX1-associated congenital neutropenia. Haematologica 13 32327498
2017 Delayed Puberty and Gonadal Failure in Patients with HAX1 Mutation. Journal of clinical immunology 13 28681255
2015 HAX-1: a novel p-body protein. DNA and cell biology 13 25289648