Affinage

DNAJB6

DnaJ homolog subfamily B member 6 · UniProt O75190

Length
326 aa
Mass
36.1 kDa
Annotated
2026-04-28
92 papers in source corpus 38 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNAJB6 is an HSP40/DNAJ family co-chaperone that functions as a potent, broad-spectrum suppressor of protein aggregation and amyloid formation, with critical roles in proteostasis, intermediate filament organization, nuclear pore complex biogenesis, and Wnt/β-catenin signaling. DNAJB6 forms dynamic oligomers whose conserved S/T residues in the C-terminal domain directly bind aggregation-prone species (polyQ, Aβ42, α-synuclein, FG-nucleoporins, FUS) at sub-stoichiometric ratios, inhibiting both primary and secondary nucleation of amyloid fibrils; its J domain activates Hsp70 to promote proteasomal clearance of misfolded clients, while a helical element in the G/F domain autoinhibits Hsp70 engagement (PMID:25217638, PMID:30024736, PMID:37797698, PMID:37923706, PMID:36302971, PMID:41271702). Dominant mutations in the G/F and J domains cause limb-girdle muscular dystrophy type 1D (LGMD1D) not by simply abolishing anti-aggregation activity but by disrupting the G/F-domain-mediated autoinhibitory regulation of Hsp70 binding, leading to uncontrolled Hsp70 hyperactivation and depletion in muscle cells (PMID:22366786, PMID:22334415, PMID:37923706). Beyond proteostasis, DNAJB6 regulates keratin 18 intermediate filament turnover via Hsp70-dependent proteasomal degradation, facilitates nuclear import of client proteins such as Slfn1, recruits class II HDACs to repress NFAT transcriptional activity, suppresses Wnt/β-catenin signaling through GSK3β activation via PP2A recruitment, and prevents FG-nucleoporin aggregation during nuclear pore complex assembly (PMID:10954706, PMID:17409114, PMID:18373498, PMID:16260608, PMID:22266849, PMID:36302971).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1999 High

    Before any biochemical role was known, knockout of the mouse ortholog Mrj revealed that DNAJB6 is essential for chorioallantoic fusion during placental development, establishing it as a developmentally required co-chaperone.

    Evidence Gene trap knockout mouse with mid-gestation lethality and trophoblast fusion failure

    PMID:10021343

    Open questions at the time
    • Molecular client(s) mediating the placental phenotype were unknown
    • Whether chaperone activity per se was required was not tested
  2. 2000 High

    Identification of keratin 18 as a direct binding partner of DNAJB6's C-terminus, and demonstration that antibody-mediated DNAJB6 inhibition specifically disorganizes K8/18 filaments, established the first defined client-specific co-chaperone function — regulation of intermediate filament organization via Hsp70.

    Evidence Yeast two-hybrid, co-immunoprecipitation, domain mapping, anti-Mrj antibody microinjection causing K8/18 disorganization

    PMID:10954706

    Open questions at the time
    • Whether keratin was the relevant client for the placental phenotype was untested
    • Mechanism of Hsp70 cooperation in filament turnover was unresolved
  3. 2002 High

    DNAJB6 was shown to suppress polyglutamine aggregation and associated toxicity in a Huntington's disease cell model, revealing its broader anti-amyloid function beyond intermediate filaments.

    Evidence Overexpression in cell-based HD model with aggregation and caspase activity readouts

    PMID:11896048

    Open questions at the time
    • Whether suppression was direct or Hsp70-dependent was unknown
    • In vivo relevance in neurodegeneration not yet tested
  4. 2005 High

    Discovery that DNAJB6 directly binds NFATc3 and recruits class II HDACs to repress NFAT transcriptional activity revealed a nuclear transcriptional regulatory function distinct from its cytoplasmic anti-aggregation role.

    Evidence Yeast two-hybrid, co-IP, ChIP showing reduced NFATc3 occupancy at TNF-α promoter, blockade of cardiomyocyte hypertrophy

    PMID:16260608

    Open questions at the time
    • Whether HDAC recruitment required Hsp70 was not determined
    • Physiological contexts beyond cardiomyocyte hypertrophy were unexplored
  5. 2007 High

    Genetic rescue of the Mrj-knockout placental phenotype by reducing keratin expression proved that keratin aggregate accumulation — not loss of other chaperone activities — causes the chorioallantoic fusion failure, directly linking DNAJB6's proteasome-dependent keratin clearance to its developmental role.

    Evidence Mrj−/− crossed with keratin-deficient embryos; chorioallantoic attachment rescued; EM showing keratin inclusion bodies

    PMID:17409114

    Open questions at the time
    • Whether DNAJB6 directs keratins to the proteasome via ubiquitin machinery was not resolved
    • Relevance of keratin turnover to human DNAJB6 disease was unknown
  6. 2008 High

    DNAJB6 was found to facilitate nuclear import of Slfn1 and suppress T-cell proliferation, demonstrating a client-specific chaperoning function in which DNAJB6 escorts proteins into the nucleus.

    Evidence Co-IP, nuclear/cytoplasmic fractionation, DNAJB6 knockdown sequestering Slfn1 in cytoplasm, transgenic mice with T-cell phenotype

    PMID:18373498

    Open questions at the time
    • Whether DNAJB6 directly interacts with nuclear import receptors was unknown
    • Generality of the nuclear import chaperone function to other clients was not tested
  7. 2012 High

    Two independent studies identified dominant G/F domain mutations as the cause of LGMD1D, establishing DNAJB6 as a disease gene; initial work attributed pathogenicity to reduced anti-aggregation activity and increased protein half-life, with interaction to the CASA complex (BAG3) also identified.

    Evidence Exome sequencing, zebrafish/cell functional testing, anti-aggregation assays, co-IP with BAG3

    PMID:22334415 PMID:22366786

    Open questions at the time
    • Whether loss of anti-aggregation activity is sufficient for disease was debated
    • Mechanism by which G/F mutations alter chaperone function was not structurally resolved
  8. 2012 Medium

    Parallel work established that DNAJB6 suppresses Wnt/β-catenin signaling by recruiting PP2A via its J domain to dephosphorylate GSK3β at Ser9, activating GSK3β and promoting β-catenin degradation, with a regulatory feedback loop through DKK1/MSX1.

    Evidence Co-IP of DNAJB6-HSPA8-PP2A complex, J domain deletion abrogating complex, ChIP and promoter analyses for DKK1/MSX1 loop

    PMID:22266849 PMID:22455953

    Open questions at the time
    • Whether GSK3β/β-catenin regulation contributes to LGMD1D pathology was untested
    • Single-lab findings for the PP2A recruitment mechanism
  9. 2013 High

    Reconstitution with purified protein demonstrated that DNAJB6 directly binds polyQ peptides as an oligomer and suppresses fibrillation at sub-stoichiometric ratios in an Hsp70-independent manner, distinguishing it mechanistically from DNAJB1.

    Evidence In vitro ThT fibrillation assay with purified DNAJB6, size analysis showing oligomers

    PMID:23612975 PMID:23904097

    Open questions at the time
    • Which residues mediate polyQ binding was unknown
    • Structural basis of oligomerization was unresolved
  10. 2014 High

    Kinetic analysis revealed that DNAJB6 inhibits both primary and secondary nucleation of Aβ42 amyloid fibrils at sub-stoichiometric ratios by interacting with aggregated rather than monomeric species, and becomes incorporated into fibrils — establishing a sacrificial inhibitor mechanism.

    Evidence ThT fluorescence, CD spectroscopy, quantitative kinetic modeling of Aβ42 aggregation curves

    PMID:25217638

    Open questions at the time
    • Residues responsible for Aβ binding were not mapped
    • Whether incorporation into fibrils limits long-term protection in vivo was unknown
  11. 2017 High

    CRISPR knockout showed DNAJB6 is essential for suppressing α-synuclein aggregation in cells, and J-domain catalytic activity (H31Q mutant) and Hsp70 are required, establishing that unlike polyQ suppression, α-synuclein clearance depends on Hsp70 cooperation.

    Evidence DNAJB6 CRISPR KO in HEK293T, rescue with WT and H31Q mutant, Hsp70 dependence assay

    PMID:28831037

    Open questions at the time
    • Whether Hsp70 dependence reflects disaggregation vs. degradation was unclear
    • Specific Hsp70 isoform involvement was not determined
  12. 2018 High

    Systematic S/T-to-A mutagenesis and structural analysis revealed that conserved S/T residues in the C-terminal domain line a peptide-binding cleft at the dimer interface of dynamic DNAJB6 oligomers and are essential for hydrogen bonding to aggregated Aβ42, providing the first structural and chemical model of client recognition.

    Evidence ThT assay with progressive S/T mutants, SPR, NMR, crosslinking-MS, EM single-particle reconstruction

    PMID:29581438 PMID:30024736

    Open questions at the time
    • Atomic-resolution structure of DNAJB6 oligomer was not obtained
    • How S/T residues distinguish different amyloid clients was not addressed
  13. 2019 High

    Loss of DNAJB6 expression upon neuronal differentiation was identified as the basis for neuronal vulnerability to polyQ aggregation, with DNAJB6 knockdown in progenitors causing spontaneous aggregation and overexpression in neurons being protective.

    Evidence iPSC-derived neurons from SCA3/HD patients, DNAJB6 knockdown/overexpression, glutamate stress

    PMID:32268123

    Open questions at the time
    • Transcriptional mechanism controlling DNAJB6 downregulation in neurons was not identified
    • Whether DNAJB6 restoration is therapeutically viable in human neurons was untested
  14. 2019 High

    DNAJB6 KO cells showed increased seeded α-synuclein aggregation that was partially reversed by proteasome inhibition, indicating DNAJB6 channels aggregated α-synuclein to proteasomal degradation rather than simply preventing nucleation.

    Evidence CRISPR KO, PFF seeding, FRET analysis, MG132 treatment

    PMID:31514384

    Open questions at the time
    • Ubiquitin ligase connecting DNAJB6 to proteasomal targeting was not identified
    • Whether autophagy also contributes was not examined
  15. 2020 High

    Native mass spectrometry directly detected DNAJB6 dimers and trimers bound to Aβ oligomers in an S/T-residue-dependent manner, providing the first direct visualization of the chaperone–client complex stoichiometry.

    Evidence Native MS detection of DNAJB6–Aβ(1-40) complexes, comparison with S/T-to-A mutant

    PMID:32350108

    Open questions at the time
    • Structural arrangement of Aβ within the complex was unresolved
    • Whether these complexes represent on-pathway intermediates for clearance was unknown
  16. 2020 High

    LGMD1D mutations were shown to enhance GSK3β activation and suppress β-catenin/NFAT3c signaling in muscle, and GSK3β inhibition with lithium rescued muscle function in a mouse model, linking the Wnt/GSK3β axis to LGMD1D pathogenesis.

    Evidence CRISPR KO myoblasts, SILAC proteomics, in vivo LiCl treatment with functional strength measures

    PMID:31123706

    Open questions at the time
    • Whether GSK3β hyperactivation is upstream or parallel to protein aggregation in LGMD1D was unresolved
    • Long-term efficacy and specificity of lithium treatment unknown
  17. 2022 High

    DNAJB6 was discovered to localize at nuclear pore complex biogenesis intermediates, bind FG-nucleoporins, and prevent their aggregation; loss of DNAJB6 caused accumulation of cytosolic annulate lamellae, establishing a new role in NPC quality control.

    Evidence Immunoelectron tomography, live imaging, DNAJB6 KO, in vitro FG-Nup aggregation assay

    PMID:36302971

    Open questions at the time
    • Whether NPC defects contribute to LGMD1D or neurodegeneration was unknown
    • How DNAJB6 is recruited specifically to NPC assembly sites was not determined
  18. 2022 High

    NMR structural analysis overturned the prevailing loss-of-function model for LGMD1D: disease mutants retain anti-aggregation activity but disrupt a helical autoinhibitory element in the G/F domain that regulates Hsp70 binding, causing uncontrolled Hsp70 hyperactivation and depletion — a toxic gain-of-function mechanism rescued by blocking DNAJB6–Hsp70 interaction.

    Evidence Solution NMR of WT vs. mutant G/F domains, Hsp70 ATPase assays, Hsp70 depletion measurements, phenotype rescue

    PMID:37923706

    Open questions at the time
    • Whether Hsp70 depletion is the sole pathogenic mechanism or cooperates with aggregation was not fully resolved
    • Structural basis of the autoinhibitory helix–J domain interaction at atomic resolution was not determined
  19. 2023 High

    Domain dissection revealed that the CTD alone inhibits secondary nucleation of Aβ42 independently of S/T residues, while S/T residues in CTD β-strand 1 are specifically required for primary nucleation inhibition and coaggregation, establishing a dual-mechanism model with separable molecular determinants.

    Evidence Kinetic assays with CTD and full-length constructs, native MS, crosslinking, SPR

    PMID:37797698

    Open questions at the time
    • Whether the dual mechanism applies to non-Aβ clients was untested
    • How full-length oligomeric architecture positions the CTD for both functions was unresolved
  20. 2025 High

    DNAJB6 was shown to co-phase separate with FUS condensates and lock them into a loose gel-like state preventing fibrilization, with in vivo validation that DNAJB6 overexpression prevents motor neuron loss in a FUS-ALS mouse model, extending its anti-aggregation repertoire to phase-separated clients.

    Evidence Biophysical characterization of condensates, deep mutational scanning, mouse FUS-ALS model with motor neuron counts

    PMID:41271702

    Open questions at the time
    • Whether DNAJB6 modulates other disease-relevant biomolecular condensates is unknown
    • Mechanism by which DNAJB6 prevents liquid-to-solid transition at the molecular level is not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the atomic-resolution structure of DNAJB6 oligomers and their client-bound states; the precise mechanism by which the G/F domain autoinhibitory helix regulates J domain–Hsp70 coupling; whether NPC biogenesis and PINK1 chaperoning roles contribute to LGMD1D or neurodegeneration; and whether therapeutic targeting of the DNAJB6–Hsp70 interface can treat LGMD1D in humans.
  • No high-resolution structure of full-length DNAJB6 oligomer exists
  • Relative contributions of Hsp70 hyperactivation vs. aggregation to disease not quantified
  • ER-SURF/PINK1 pathway role awaits peer-reviewed confirmation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 9 GO:0098772 molecular function regulator activity 4 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005635 nuclear envelope 1 GO:0005730 nucleolus 1
Pathway
R-HSA-392499 Metabolism of proteins 12 R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9609507 Protein localization 2
Partners
BAG3DCTN1HSPA1AHSPA8KRT18NFATC3PPP2CASLFN1
Complex memberships
CASA complex (via BAG3)

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 DNAJB6 co-chaperone mutations (p.Phe93Leu, p.Phe89Ile) in the G/F domain cause LGMD1D via dominant toxic effect mediated specifically by the cytoplasmic isoform; mutations increase DNAJB6 half-life and reduce its anti-aggregation activity; DNAJB6 interacts with members of the CASA complex including BAG3. In vivo functional testing in zebrafish/cell models, in vitro half-life and anti-aggregation assays, co-immunoprecipitation with CASA complex members Nature genetics High 22366786
2012 DNAJB6 G/F domain mutations cause dominantly inherited myopathy with abnormal aggregation of proteins including TDP-43; the G/F domain is a mutational hotspot critical for DNAJB6 chaperone function. Exome sequencing, genome-wide linkage analysis, immunohistochemistry of patient muscle Annals of neurology High 22334415
2013 Purified DNAJB6 forms large heterogeneous oligomers and directly binds polyQ peptides at substoichiometric molar ratios to suppress fibrillation in an ATP- and HSPA1-independent manner; DNAJB1 lacks this activity. In vitro thioflavin T fibrillation assay with purified proteins, size analysis Cell stress & chaperones High 23904097
2013 DNAJB6 (and DNAJB8) prevent intracellular polyQ peptide aggregation by directly binding the polyQ tract; HSPA/Hsp70 and DNAJB1 do not prevent peptide-initiated aggregation; DNAJB6 affects soluble levels of polyQ peptides. Cell-based expression of polyQ peptides, fluorescence microscopy, comparison of chaperone family members The Journal of biological chemistry High 23612975
2014 DNAJB6 inhibits Aβ42 amyloid formation at highly sub-stoichiometric ratios by interacting with aggregated (not monomeric) forms of Aβ42, preventing fibril growth and inhibiting both primary and secondary nucleation; DNAJB6 becomes incorporated into growing fibrils and is gradually depleted. Thioflavin T fluorescence, far-UV CD spectroscopy, quantitative kinetic analysis, immunochemistry The Journal of biological chemistry High 25217638
1999 Mrj (mouse DNAJB6 ortholog) is essential for chorioallantoic fusion during placental development; Mrj null mice die at mid-gestation due to failure of trophoblast fusion, with reduced expression of chorionic transcription factors Err2 and Gcm1. Gene trap knockout mouse, developmental analysis, in situ hybridization Development (Cambridge, England) High 10021343
2002 MRJ (DNAJB6) is a brain-enriched DnaJ-like chaperone that suppresses polyglutamine-dependent protein aggregation, caspase activity, and cellular toxicity in an in vitro HD cell model. Cell-based HD model, overexpression, aggregation assay, caspase activity measurement The Journal of biological chemistry High 11896048
2000 Mrj/DNAJB6 directly binds keratin 18 (K18) through its C-terminus and interacts with Hsp/c70 via its N-terminal J domain; microinjection of anti-Mrj antibody causes disorganization of K8/18 filaments without affecting actin or microtubules, establishing Mrj as a K18-specific co-chaperone regulating intermediate filament organization. Yeast two-hybrid, co-immunoprecipitation, immunostaining, microinjection of antibody The Journal of biological chemistry High 10954706
2005 Mrj/DNAJB6 interacts directly with NFATc3 via the rel homology domain (identified by yeast two-hybrid and confirmed in mammalian cells); Mrj recruits class II histone deacetylases (HDACs) to repress NFAT transcriptional activity in the nucleus upon heat shock; Mrj decreases NFATc3 occupancy at the TNF-α promoter and blocks calcineurin-induced cardiomyocyte hypertrophy. Yeast two-hybrid, co-immunoprecipitation in mammalian cells, in vitro binding, ChIP, siRNA knockdown, cardiomyocyte hypertrophy assay Molecular and cellular biology High 16260608
2007 Mrj (mouse DNAJB6) co-chaperone is required for proteasome-mediated degradation of keratin 18; Mrj null placenta accumulates keratin inclusion bodies in chorionic trophoblast cells preventing chorioallantoic attachment; reducing keratin expression in Mrj-/- conceptuses rescues chorioallantoic attachment, demonstrating keratin aggregate cytotoxicity as the mechanism. Mouse knockout, keratin-deficient embryo rescue genetics, histochemistry, electron microscopy Development (Cambridge, England) High 17409114
2008 DNAJB6 binds Schlafen1 (Slfn1) and stabilizes it together with Hsp70, and critically enhances nuclear import of Slfn1; DNAJB6 knockdown sequesters Slfn1 in cytoplasm and abolishes cell-cycle arrest; transgenic DNAJB6 in T-cells promotes Slfn1 nuclear import, suppresses T-cell proliferation via cyclin D1 downregulation. Co-immunoprecipitation, knockdown, overexpression, nuclear/cytoplasmic fractionation, T-cell proliferation assay, transgenic mice The Biochemical journal High 18373498
2008 DNAJB6 large isoform (MRJ-L) contains a functional nuclear localization sequence and localizes to the nucleus; its nuclear localization is required for tumor suppression of breast cancer migration, invasion, and orthotopic tumor growth. Exogenous expression, subcellular localization analysis, migration/invasion assays, mouse xenograft Breast cancer research : BCR Medium 18328103
2010 DNAJB6 large isoform (MRJ-L) induces degradation of β-catenin by upregulating DKK1, a Wnt/β-catenin signaling inhibitor, leading to partial reversal of mesenchymal phenotype and downregulation of mesenchymal markers. Overexpression, Western blot for β-catenin and EMT markers, DKK1 expression analysis The Journal of biological chemistry Medium 20522561
2012 DNAJB6 J domain is required for its tumor-suppressive function; DNAJB6 binds HSPA8 (HSC70) and recruits PP2A to cause dephosphorylation of GSK3β at Ser9, activating GSK3β, leading to β-catenin degradation and loss of TCF/LEF-mediated OPN transcription; J domain deletion abrogates this multiprotein complex. Co-immunoprecipitation, phosphorylation assays, J domain deletion mutagenesis, in vitro and in vivo functional analyses Oncogene Medium 22266849
2012 DNAJB6 upregulates DKK1 transcription through a mechanism involving MSX1; DNAJB6 silencing upregulates MSX1 with β-catenin stabilization; β-catenin binds and activates the MSX1 promoter; MSX1 represses DKK1 defining a DNAJB6/β-catenin/MSX1/DKK1 regulatory loop. ChIP assay, promoter analysis, siRNA silencing, transcription reporter assays The Biochemical journal Medium 22455953
2017 DNAJB6 suppression of α-synuclein aggregation requires its J-domain (catalytically inactive H31Q mutant fails to suppress aggregation) and is dependent on Hsp70; CRISPR/Cas9 knockout of DNAJB6 in HEK293T cells causes massive increase in α-syn aggregation, rescued by DNAJB6 re-introduction. CRISPR/Cas9 KO, re-introduction rescue, J-domain mutant (H31Q) functional analysis, Hsp70 dependence assay Scientific reports High 28831037
2018 Conserved S/T residues in DNAJB6 are essential for inhibition of Aβ42 fibril formation; progressive S/T-to-A substitutions progressively reduce suppression of primary nucleation and binding to Aβ42; S/T residues mediate hydrogen bonding with aggregated Aβ42 species. Thioflavin T fluorescence assay, surface plasmon resonance, microscale thermophoresis, NMR spectroscopy, progressive mutagenesis Biochemistry High 30024736
2018 DNAJB6 forms oligomers with a peptide-binding cleft lined with S/T residues at the dimer interface; cross-linking mass spectrometry and electron microscopy structural analysis revealed elongated particles (160×120 Å); oligomers are dynamic entities that exchange subunits. Crosslinking mass spectrometry, homology modeling, SAXS, electron microscopy, single particle reconstruction, mixed-isotope crosslinking Scientific reports High 29581438
2019 DNAJB6b knockdown in neural progenitor cells causes spontaneous polyQ aggregation; loss of DNAJB6 expression upon neuronal differentiation (confirmed in vivo) underlies neuronal hypersensitivity to amyloidogenesis; upregulation of DNAJB6 in neurons antagonizes glutamate-induced polyQ aggregation. iPSC-derived neurons and progenitors, DNAJB6 knockdown, overexpression, iPSC lines from SCA3 and HD patients, glutamate treatment aggregation model Molecular cell High 32268123
2019 DNAJB6 (but not DNAJB1) suppresses seeded α-synuclein aggregation in cells; DNAJB6 KO cells show significantly more PFF-induced α-syn aggregates; proteasomal inhibitor MG132 diminishes the increased aggregation in DNAJB6 KO cells, suggesting DNAJB6 targets aggregated α-syn for proteasomal degradation. CRISPR/Cas9 KO, α-syn PFF seeding, fluorescence microscopy, FRET analysis, proteasome inhibition International journal of molecular sciences High 31514384
2019 DNAJB6 interacts with dynactin subunit p150Glued (DCTN1) in a RanGTP-dependent manner specifically in M-phase, and promotes spindle pole focusing and dynein force generation during mitosis. RanGTP-regulated interaction assay, co-immunoprecipitation in M-phase, spindle pole focusing analysis Journal of cell science Medium 31064815
2020 DNAJB6 WT captures oligomeric forms of Aβ(1-40) via its S/T residues; native MS directly detected DNAJB6 dimers and trimers bound to varying amounts of Aβ; S/T-to-A mutant DNAJB6 does not reduce Aβ oligomer signals, confirming S/T residues are required for oligomer capture and prevention of primary nucleation. Native mass spectrometry, direct detection of DNAJB6-Aβ complexes, S/T mutant comparison The Journal of biological chemistry High 32350108
2020 DNAJB6 KO leads to accumulation of sarcomeric proteins and hypertrophic myotubes with enhanced fusion; LGMD1D mutations in DNAJB6 enhance GSK3β activation and suppress β-catenin and NFAT3c signaling; GSK3β inhibition with lithium chloride improves muscle size and strength in LGMD1D mouse model. CRISPR/Cas9 KO myoblasts, quantitative mass spectrometry (SILAC), immunohistochemistry, immunoblot, mouse functional strength measures, LiCl treatment Neurology. Genetics High 31123706
2020 DNAJB6 and DNAJA1 modulate polyQ aggregation in opposite manners: DNAJB6 KO causes 5-fold increase and DNAJA1 KO causes 4-fold decrease in polyQ74htt aggregation; DNAJB6 KO increases cell death. CRISPR/Cas9 KO of individual DNAJ genes, fluorescence microscopy, filter trap assay, trypan blue/PI viability assay Scientific reports Medium 32424160
2021 In vivo AAV-mediated co-expression of DNAJB6b in rat substantia nigra suppresses α-synuclein-induced dopaminergic cell death and PD-related motor deficits; DNAJB6 prevents α-syn PFF-induced aggregation in cells. AAV6 injection in rat SNpc, motor behavior testing (stepping test), dopaminergic cell counting, FRET assay in α-syn CFP/YFP cells Neurobiology of disease High 34390836
2022 DNAJB6 forms foci near nuclear pore complexes (NPCs), binds FG-nucleoporins, and prevents their aggregation in vitro and in cells; loss of DNAJB6 causes accumulation of cytosolic annulate lamellae (partly assembled NPCs); DNAJB6 localizes inside herniation lumen at NPC biogenesis intermediates by immunoelectron tomography. Immunoelectron tomography, live imaging, DNAJB6 KO, in vitro FG-Nup aggregation assay, electron microscopy Nature cell biology High 36302971
2022 DNAJB6 LGMD1D disease mutants do not show reduced aggregation-prevention activity in vitro but structurally differ from WT in the G/F domain; a helical element in WT DNAJB6 regulates its Hsp70 binding, and disease mutants disrupt this regulation, causing unregulated Hsp70 hyperactivation and Hsp70 depletion in myocytes; interfering with DNAJB6-Hsp70 binding reverses the disease phenotype. Solution NMR, biochemical interaction assays, in vitro aggregation assay, Hsp70 depletion measurement, phenotype rescue Nature communications High 37923706
2022 The T193A mutation in the C-terminal domain (CTD) of DNAJB6 minimally affects CTD structure but increases the population and rate of formation of a partially folded state via β-strand peptide plane flips (~100 μs timescale), altering CTD oligomerization and anti-aggregation activity. Solution NMR, relaxation-based methods, dynamics analysis Angewandte Chemie (International ed. in English) High 35247211
2023 The C-terminal domain (CTD) of DNAJB6 binds to Aβ42 fibrils and inhibits secondary nucleation independently of S/T residues; inhibition of primary nucleation requires the full-length protein or regions outside the CTD and depends on S/T residues; S/T residues in CTD β-strand 1 mediate coaggregation with Aβ for primary nucleation inhibition. In vitro kinetic assays, native MS, chemical crosslinking, surface plasmon resonance, domain dissection constructs The Journal of biological chemistry High 37797698
2010 DNAJB6 (MRJ) interacts with urokinase receptor (uPAR) identified by yeast two-hybrid; C-terminal region of MRJ is required for uPAR interaction; MRJ overexpression enhances uPAR-mediated cell adhesion to vitronectin. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, deletion mapping, cell adhesion assay International journal of oncology Medium 20372789
2012 MRJ(S)/DNAJB6 small isoform translocates to the nucleus in response to heat shock and hypoxia in an NLS-independent manner; a 20-amino acid C-terminal stretch functions as a stress-sensing region; constitutive nuclear localization of MRJ(S) promotes malignant attributes. Nuclear/cytoplasmic fractionation, deletion analysis, heat shock/hypoxia stimulation, functional invasion/proliferation assays Experimental cell research Medium 22504047
2008 Mrj protein is upregulated in M-phase of HeLa cells and localizes to the nucleolus during interphase, dispersing throughout the cell during late mitosis; cell cycle-specific expression and localization regulate Mrj activity. Cell cycle synchronization, Western blot, immunostaining Molecular and cellular biochemistry Low 19002655
2016 DNAJB6b (long isoform) was identified as a cardiomyopathy susceptibility gene in zebrafish; loss-of-function modifying effects are ameliorated by inhibition of ER stress; overexpression of DNAJB6L exerts cardioprotective effects in both zebrafish and mouse cardiomyopathy models. Zebrafish insertional mutagenesis screen, doxorubicin stress, ER stress inhibition, mouse CM model, overexpression JCI insight Medium 27642634
2022 Disease-analogous mutations in yeast DNAJB6 homolog Sis1 alter client protein aggregate structure, interfere with the Hsp70 ATPase cycle, reduce dimerization, and poison wild-type Sis1 function in a substrate-conformer-specific manner. Yeast prion model, in vitro chaperone activity assays, ATPase cycle analysis, dimerization assay Nature communications High 35931773
2019 DNAJB6 interacts with JEV NS3 protein (identified by yeast two-hybrid, confirmed by colocalization and co-immunoprecipitation) and has a negative regulatory function in JEV replication; loss of DNAJB6 function significantly increases viral replication without affecting viral binding or internalization. Yeast two-hybrid screen, co-immunoprecipitation, colocalization, siRNA knockdown, viral replication assay International journal of molecular sciences Medium 31739611
2025 DNAJB6 co-phase separates with FUS-containing condensates and locks them into a loose gel-like state preventing fibrilization; DNAJB6 overexpression prevents motor neuron loss and microglia activation in a mouse FUS-ALS model; domain mapping and deep mutational scan identified key residues required for anti-aggregation activity. Yeast genetic screening, biophysical characterization of condensates, mouse FUS-ALS model, deep mutational scanning Nature communications High 41271702
2024 ER membrane-tethered DNAJB6 shields the PINK1 precursor protein in transit from the ER to mitochondria (via the ER-SURF pathway); loss of DNAJB6 leads to persistence of ER/endolysosome-associated PINK1 precursor stores and failure of mitophagy upon mitochondrial damage. Live-cell imaging of PINK1 precursor translation, DNAJB6 loss-of-function, mitophagy assay bioRxivpreprint Medium
2019 DNAJB6 mutant proteins (p.F91I, p.F91L) show significantly reduced ability to prevent polyQ-huntingtin aggregation in filter-trap assay, confirming loss of anti-aggregation chaperone function as the disease mechanism for severe LGMD1D. Filter-trap aggregation assay in mammalian cells with polyQ-huntingtin model, transient transfection Neuromuscular disorders : NMD Medium 26338452
2019 J domain mutations in DNAJB6 (p.A50V and p.E54A) cause dominant distal myopathy and show reduced anti-aggregation capacity by filter trap assay and TDP-43 disaggregation assays; mutated residues are in close proximity to the G/F domain based on structural modeling. Filter trap assay, TDP-43 disaggregation assay, protein structural modeling Neuromuscular disorders : NMD Medium 31955980

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. Nature genetics 215 22366786
2014 Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation. The Journal of biological chemistry 150 25217638
2012 Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy. Annals of neurology 138 22334415
2019 CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer. Molecular cancer 123 31623606
2013 The DNAJB6 and DNAJB8 protein chaperones prevent intracellular aggregation of polyglutamine peptides. The Journal of biological chemistry 120 23612975
2013 DNAJB6 is a peptide-binding chaperone which can suppress amyloid fibrillation of polyglutamine peptides at substoichiometric molar ratios. Cell stress & chaperones 98 23904097
1999 Mrj encodes a DnaJ-related co-chaperone that is essential for murine placental development. Development (Cambridge, England) 97 10021343
2002 Characterization of a brain-enriched chaperone, MRJ, that inhibits Huntingtin aggregation and toxicity independently. The Journal of biological chemistry 95 11896048
2005 The DnaJ-related factor Mrj interacts with nuclear factor of activated T cells c3 and mediates transcriptional repression through class II histone deacetylase recruitment. Molecular and cellular biology 86 16260608
2017 The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation. Scientific reports 82 28831037
2008 Large isoform of MRJ (DNAJB6) reduces malignant activity of breast cancer. Breast cancer research : BCR 81 18328103
2000 Identification of Mrj, a DnaJ/Hsp40 family protein, as a keratin 8/18 filament regulatory protein. The Journal of biological chemistry 80 10954706
2020 DNAJB6, a Key Factor in Neuronal Sensitivity to Amyloidogenesis. Molecular cell 66 32268123
2009 DnaJB6 is present in the core of Lewy bodies and is highly up-regulated in parkinsonian astrocytes. Journal of neuroscience research 59 18711724
2015 Nuclear Localization of DNAJB6 Is Associated With Survival of Patients With Esophageal Cancer and Reduces AKT Signaling and Proliferation of Cancer Cells. Gastroenterology 54 26302489
2012 DNAJB6 chaperones PP2A mediated dephosphorylation of GSK3β to downregulate β-catenin transcription target, osteopontin. Oncogene 53 22266849
2018 Conserved S/T Residues of the Human Chaperone DNAJB6 Are Required for Effective Inhibition of Aβ42 Amyloid Fibril Formation. Biochemistry 52 30024736
2010 DNAJB6 induces degradation of beta-catenin and causes partial reversal of mesenchymal phenotype. The Journal of biological chemistry 51 20522561
2007 The Mrj co-chaperone mediates keratin turnover and prevents the formation of toxic inclusion bodies in trophoblast cells of the placenta. Development (Cambridge, England) 50 17409114
2019 DNAJB6 Promotes Ferroptosis in Esophageal Squamous Cell Carcinoma. Digestive diseases and sciences 48 31701262
2013 DNAJB6 myopathy in an Asian cohort and cytoplasmic/nuclear inclusions. Neuromuscular disorders : NMD 47 23394708
2008 The Hsp40 family chaperone protein DnaJB6 enhances Schlafen1 nuclear localization which is critical for promotion of cell-cycle arrest in T-cells. The Biochemical journal 47 18373498
2015 Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy. Acta neuropathologica communications 44 26205529
2020 Co-chaperones DNAJA1 and DNAJB6 are critical for regulation of polyglutamine aggregation. Scientific reports 43 32424160
2018 Structural modelling of the DNAJB6 oligomeric chaperone shows a peptide-binding cleft lined with conserved S/T-residues at the dimer interface. Scientific reports 43 29581438
2022 The chaperone DNAJB6 surveils FG-nucleoporins and is required for interphase nuclear pore complex biogenesis. Nature cell biology 41 36302971
2020 Amyloid-β oligomers are captured by the DNAJB6 chaperone: Direct detection of interactions that can prevent primary nucleation. The Journal of biological chemistry 41 32350108
2006 A Drosophila ortholog of the human MRJ modulates polyglutamine toxicity and aggregation. Neurobiology of disease 40 16934481
2012 DNAJB6 governs a novel regulatory loop determining Wnt/β-catenin signalling activity. The Biochemical journal 39 22455953
2019 The Molecular Chaperone DNAJB6, but Not DNAJB1, Suppresses the Seeded Aggregation of Alpha-Synuclein in Cells. International journal of molecular sciences 38 31514384
2016 A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene. JCI insight 38 27642634
2016 Diagnostically important muscle pathology in DNAJB6 mutated LGMD1D. Acta neuropathologica communications 34 26847086
2014 Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy. Neuromuscular disorders : NMD 33 24594375
2015 Novel mutations in DNAJB6 gene cause a very severe early-onset limb-girdle muscular dystrophy 1D disease. Neuromuscular disorders : NMD 32 26338452
2021 DNAJB6 suppresses alpha-synuclein induced pathology in an animal model of Parkinson's disease. Neurobiology of disease 31 34390836
2016 Emerging roles and underlying molecular mechanisms of DNAJB6 in cancer. Oncotarget 31 27276715
2016 DNAJB6 Myopathies: Focused Review on an Emerging and Expanding Group of Myopathies. Frontiers in molecular biosciences 31 27747217
2012 Micro-RNA-632 downregulates DNAJB6 in breast cancer. Laboratory investigation; a journal of technical methods and pathology 31 22710984
2023 DNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones. Nature communications 30 37923706
2014 Overexpression of DNAJB6 promotes colorectal cancer cell invasion through an IQGAP1/ERK-dependent signaling pathway. Molecular carcinogenesis 30 25044025
2013 'Pathognomonic' muscle imaging findings in DNAJB6 mutated LGMD1D. European journal of neurology 29 23865856
2016 Genetic interaction of hnRNPA2B1 and DNAJB6 in a Drosophila model of multisystem proteinopathy. Human molecular genetics 26 26744327
2014 Heat shock proteins HSP70 and MRJ cooperatively regulate cell adhesion and migration through urokinase receptor. BMC cancer 25 25175595
2009 Neural stem cell self-renewal requires the Mrj co-chaperone. Developmental dynamics : an official publication of the American Association of Anatomists 25 19777589
1999 Cloning, tissue expression, and chromosomal assignment of human MRJ gene for a member of the DNAJ protein family. Journal of human genetics 25 10319584
2019 Mutations in the J domain of DNAJB6 cause dominant distal myopathy. Neuromuscular disorders : NMD 24 31955980
2018 Astrocytic expression of the chaperone DNAJB6 results in non-cell autonomous protection in Huntington's disease. Neurobiology of disease 24 30408590
2015 A novel mutation in DNAJB6, p.(Phe91Leu), in childhood-onset LGMD1D with a severe phenotype. Neuromuscular disorders : NMD 24 26371419
2011 Cell-cell adhesion defects in Mrj mutant trophoblast cells are associated with failure to pattern the chorion during early placental development. Developmental dynamics : an official publication of the American Association of Anatomists 23 21972064
2018 Novel mutations in DNAJB6 cause LGMD1D and distal myopathy in French families. European journal of neurology 22 29437287
2019 Hsp40 Protein DNAJB6 Interacts with Viral NS3 and Inhibits the Replication of the Japanese Encephalitis Virus. International journal of molecular sciences 20 31739611
2019 The Host Heat Shock Protein MRJ/DNAJB6 Modulates Virus Infection. Frontiers in microbiology 20 31921062
2015 Evaluation of the amyloid beta-GFP fusion protein as a model of amyloid beta peptides-mediated aggregation: a study of DNAJB6 chaperone. Frontiers in molecular neuroscience 19 26283911
2014 DNAJB6 myopathy: a vacuolar myopathy with childhood onset. Muscle & nerve 19 24170373
2010 Interaction between urokinase receptor and heat shock protein MRJ enhances cell adhesion. International journal of oncology 18 20372789
2022 Microsecond Backbone Motions Modulate the Oligomerization of the DNAJB6 Chaperone. Angewandte Chemie (International ed. in English) 17 35247211
2017 A novel DNAJB6 mutation causes dominantly inherited distal-onset myopathy and compromises DNAJB6 function. Clinical genetics 17 28233300
2011 Four new Finnish families with LGMD1D; refinement of the clinical phenotype and the linked 7q36 locus. Neuromuscular disorders : NMD 17 21376592
2023 The C-terminal domain of the antiamyloid chaperone DNAJB6 binds to amyloid-β peptide fibrils and inhibits secondary nucleation. The Journal of biological chemistry 15 37797698
2019 Lithium chloride corrects weakness and myopathology in a preclinical model of LGMD1D. Neurology. Genetics 15 31123706
2018 Interference of DNAJB6/MRJ Isoform Switch by Morpholino Inhibits Replication of HIV-1 and RSV. Molecular therapy. Nucleic acids 14 30641477
2008 Cell cycle specific expression and nucleolar localization of human J-domain containing co-chaperone Mrj. Molecular and cellular biochemistry 13 19002655
2022 A phenotype-based forward genetic screen identifies Dnajb6 as a sick sinus syndrome gene. eLife 12 36255053
2018 LGMD1D myopathy with cytoplasmic and nuclear inclusions in a Saudi family due to DNAJB6 mutation. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology 12 30838352
2023 miR-632 Induces DNAJB6 Inhibition Stimulating Endothelial-to-Mesenchymal Transition and Fibrosis in Marfan Syndrome Aortopathy. International journal of molecular sciences 11 37894814
2019 Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type. European journal of medical genetics 10 31034989
2018 Human DnaJB6 Antiamyloid Chaperone Protects Yeast from Polyglutamine Toxicity Separately from Spatial Segregation of Aggregates. Molecular and cellular biology 10 30224519
2020 Porcine DNAJB6 promotes PCV2 replication via enhancing the formation of autophagy in host cells. Veterinary research 9 32381067
2015 Cell and Context-Dependent Effects of the Heat Shock Protein DNAJB6 on Neuronal Survival. Molecular neurobiology 9 26476842
2018 Two Korean Families with Limb-Girdle Muscular Dystrophy Type 1D Associated with DNAJB6 Mutations. Yonsei medical journal 8 29869469
2012 Cellular stress stimulates nuclear localization signal (NLS) independent nuclear transport of MRJ. Experimental cell research 8 22504047
2023 DNAJB6 isoform specific knockdown: Therapeutic potential for limb girdle muscular dystrophy D1. Molecular therapy. Nucleic acids 7 37346979
2020 Long non-coding RNA Hsp4 alleviates lipopolysaccharide-induced apoptosis of lung epithelial cells via miRNA-466m-3p/DNAjb6 axis. Experimental and molecular pathology 7 32976821
2019 DnaJB6 is a RanGTP-regulated protein required for microtubule organization during mitosis. Journal of cell science 7 31064815
2022 Disease-associated mutations within the yeast DNAJB6 homolog Sis1 slow conformer-specific substrate processing and can be corrected by the modulation of nucleotide exchange factors. Nature communications 6 35931773
2024 Human milk exosome-derived circDNAJB6 improves bronchopulmonary dysplasia model by promoting DNAJB6 gene transcription. Journal of bioenergetics and biomembranes 5 38244155
2024 Mrj is a chaperone of the Hsp40 family that regulates Orb2 oligomerization and long-term memory in Drosophila. PLoS biology 5 38648719
2024 DNAJB6 is expressed in neurons and oligodendrocytes of the human brain. Glia 5 39228066
2022 DNAJB6-Containing Extracellular Vesicles as Chaperone Delivery Systems: A Proteomic Analysis. Pharmaceutics 5 36432676
2017 The Short Isoform of DNAJB6 Protects against 1-Methyl-4-phenylpridinium Ion-Induced Apoptosis in LN18 Cells via Inhibiting Both ROS Formation and Mitochondrial Membrane Potential Loss. Oxidative medicine and cellular longevity 5 28280525
2017 Characteristic Posterior-dominant Lower Limb Muscle Involvement in Limb-girdle Muscular Dystrophy due to a DNAJB6 Phe93Leu Mutation. Internal medicine (Tokyo, Japan) 4 28794355
2023 MUC1 promotes lymph node metastasis in esophageal squamous cell carcinoma by downregulating DNAJB6 expression. Environmental toxicology 3 37584547
2024 Abnormally High Expression of DNAJB6 Accelerates Malignant Progression of Lung Adenocarcinoma. Biomedicines 2 39335495
2022 Case Report: A Novel Splice-Site Mutation in DNAJB6 Associated With Juvenile-Onset Proximal-Distal Myopathy in a Chinese Patient. Frontiers in genetics 2 35812750
2025 Dual targeting of the Wnt and DNAJB6/MRJ regulatory loop as an anti-RSV strategy. Virology 1 40737980
2025 Multiplex neurodegeneration proteotoxicity platform reveals DNAJB6 promotes non-toxic FUS condensate gelation and inhibits neurotoxicity. Nature communications 1 41271702
2022 A female carrier of spinal and bulbar muscular atrophy diagnosed with DNAJB6-related distal myopathy. Journal of human genetics 1 35165376
2022 Human J-Domain Protein DnaJB6 Protects Yeast from [PSI+] Prion Toxicity. Biology 1 36552355
2022 Microsecond Backbone Motions Modulate the Oligomerization of the DNAJB6 Chaperone. Angewandte Chemie (Weinheim an der Bergstrasse, Germany) 1 38505697
2016 Heat shock protein HSP40 family chaperone DNAJB6/MRJ expression analysis in blood cells obtained from patients with atopic dermatitis in different phases. Patologicheskaia fiziologiia i eksperimental'naia terapiia 1 29244458
2026 Novel cell-based assay enables FRET-based measurements of the dimerization activity of the chaperone DNAJB6. Biology methods & protocols 0 41717343
2025 DNAJB6: A guardian against neurodegeneration. Neural regeneration research 0 40536953