Affinage

DNAJB2

DnaJ homolog subfamily B member 2 · UniProt P25686

Length
324 aa
Mass
35.6 kDa
Annotated
2026-06-09
15 papers in source corpus 8 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNAJB2 (HSJ1) is a neuronal Hsp40-family co-chaperone that maintains proteostasis by coupling Hsc70-dependent chaperone activity to the ubiquitin-proteasome system (PMID:15936278). It combines a J-domain that stimulates substrate loading onto Hsc70 with ubiquitin interaction motifs (UIMs) that bind ubiquitylated chaperone clients; through these activities HSJ1 prevents client aggregation, shields clients from deubiquitylation, and sorts them to the proteasome, including during ERAD (PMID:15936278). This chaperone function is negatively regulated by CK2-mediated phosphorylation of UIM2 at the dominant Ser250 and hierarchical Ser247 sites, which reduces ubiquitin-client binding (PMID:28031292). The J-domain is required for HSJ1b stability and its anti-aggregation function, as its deletion causes protein aggregation, increased cell death, and altered tau and BDNF levels (PMID:27449489). HSJ1 acts as an essential balancing factor in polyglutamine proteostasis: expanded ataxin-7 and huntingtin fragments sequester it into inclusions in a UIM-dependent manner, disrupting ataxin-3 homeostasis (PMID:33837238). Loss-of-function mutations in DNAJB2 cause distal hereditary motor neuropathy, and HSJ1 overexpression protects motor neurons against mutant SOD1-A4V aggregation (PMID:22522442).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1996 High

    Established an early biochemical readout of HSJ1's interaction with the Hsc70 chaperone machinery by showing it modulates Hsc70-catalysed clathrin uncoating.

    Evidence in vitro clathrin uncoating assay and coated-vesicle fractionation with quantitative ELISA

    PMID:8870655

    Open questions at the time
    • Did not define the physiological substrate range
    • Relationship between uncoating inhibition and later-defined ubiquitin shuttling role unresolved
  2. 2005 High

    Defined the core mechanism: HSJ1 bridges Hsc70 chaperone activity to the ubiquitin-proteasome system via a J-domain plus UIMs, acting as a shuttling factor for ubiquitylated clients.

    Evidence functional biochemical assays, co-IP, and cellular proteotoxicity models

    PMID:15936278

    Open questions at the time
    • Specific client spectrum in neurons not fully enumerated
    • Regulation of the activity not addressed
  3. 2012 Medium

    Connected DNAJB2 to human disease, showing loss-of-function causes distal hereditary motor neuropathy and that HSJ1 protects against motor-neuron protein aggregation.

    Evidence homozygosity mapping, splice mutation characterization, and SOD1-A4V neuronal aggregation rescue

    PMID:22522442

    Open questions at the time
    • Mechanism linking proteostasis failure to selective motor neuron loss unresolved
    • Cellular model rather than in vivo confirmation
  4. 2016 Medium

    Demonstrated the J-domain is required for HSJ1b protein stability and anti-aggregation function, linking domain loss to autophagy and reduced tau/BDNF.

    Evidence J-domain deletion cellular assays with aggregation, cell-death, and autophagy readouts

    PMID:27449489

    Open questions at the time
    • Direct mechanism by which J-domain loss destabilizes the protein not defined
    • Tau and BDNF reductions correlative
  5. 2017 High

    Identified a regulatory switch: CK2 phosphorylation of UIM2 at Ser250/Ser247 suppresses ubiquitin-client binding and chaperone activity.

    Evidence in vitro kinase assay, phospho-site mutagenesis, phospho-specific antibody, and CK2 inhibitor treatment

    PMID:28031292

    Open questions at the time
    • Physiological signals controlling CK2 activity toward HSJ1 unknown
    • In vivo consequence of phospho-regulation not tested
  6. 2021 Medium

    Showed HSJ1 is a limiting factor in polyglutamine proteostasis, being sequestered into inclusions by expanded ataxin-7 and huntingtin in a UIM-dependent manner.

    Evidence cellular aggregation models, reciprocal co-IP, and UIM deletion mutants

    PMID:33837238

    Open questions at the time
    • Quantitative threshold of sequestration for dysfunction undefined
    • Single-lab cellular evidence
  7. 2025 Low

    Extended putative DNAJB2 roles beyond classical proteostasis into ER-stress inflammatory signaling and patient cell expression regulation, and toward nuclear pore quality control.

    Evidence rosacea overexpression model with NF-κB markers; patient fibroblast heat-shock/cystamine western blots; FG-Nup phase transition assays (preprint)

    PMID:40035989 PMID:40423229

    Open questions at the time
    • Overexpression-only with marker readouts, no mechanistic reconstitution
    • Single patient-derived cell line for expression studies
    • FG-Nup role based on preprint focused on DNAJB6

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CK2 phospho-regulation, client selection, and the J-domain/UIM functional cycle are coordinated in vivo to protect specific neuronal populations remains open.
  • No in vivo model linking phospho-regulation to neuropathy
  • Full neuronal client repertoire unmapped
  • Structural basis of UIM-ubiquitin and J-Hsc70 coupling not resolved in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0044183 protein folding chaperone 2 GO:0060090 molecular adaptor activity 1
Pathway
R-HSA-392499 Metabolism of proteins 1
Partners
HSPA8

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 HSJ1 (DNAJB2) isoforms function as neuronal shuttling factors for ubiquitylated proteins, combining a J-domain that stimulates substrate loading onto Hsc70 with ubiquitin interaction motifs (UIMs) that bind ubiquitylated chaperone clients. HSJ1 prevents client aggregation, shields clients against chain trimming by ubiquitin hydrolases, and stimulates their sorting to the proteasome, participating in ERAD. Functional biochemical assays, co-immunoprecipitation, cellular proteotoxicity models Current biology : CB High 15936278
1996 HSJ1a and HSJ1b proteins inhibit hsc70-catalysed clathrin uncoating by over 40% in vitro. This inhibition correlates with an increase in hsc70 associated with the coated vesicle fraction, suggesting a non-productive stabilization of hsc70 with a coated vesicle component, and is not due to ADP binding by hsc70 or hsc70 aggregation. Quantitative two-site ELISA for clathrin triskelions, in vitro uncoating assay, coated vesicle fractionation The Biochemical journal High 8870655
2017 Protein kinase CK2 phosphorylates HSJ1 (DNAJB2) within its second UIM domain at the dominant site Ser250 and hierarchical site Ser247. Phosphorylation at these sites reduces HSJ1's ability to bind ubiquitylated clients and exert chaperone activity, as shown by phospho-site mutation and CK2-specific inhibitor treatment. Phospho-site mutagenesis, phospho-specific antibody, CK2 inhibitor treatment, ubiquitin-binding assays, in vitro kinase assay Human molecular genetics High 28031292
2021 HSJ1 (DNAJB2) is an essential factor orchestrating the proteostasis balance of ataxin-3. Polyglutamine-expanded proteins (ataxin-7 and huntingtin fragments) sequester HSJ1 into aggregates/inclusions in a UIM domain-dependent manner, thereby impairing HSJ1 function and disrupting ataxin-3 proteostasis. Cellular aggregation models, co-immunoprecipitation, UIM domain deletion mutants, immunofluorescence Scientific reports Medium 33837238
2012 Loss-of-function of HSJ1 (DNAJB2) due to a homozygous splice mutation causes distal hereditary motor neuropathy. Overexpression of both HSJ1a and HSJ1b isoforms reduced inclusion formation induced by mutated SOD1-A4V in a neuronal cellular model, demonstrating a protective role against protein aggregation in motor neurons. Cellular model of motor neuron disease (SOD1-A4V overexpression), homozygosity mapping, splice mutation characterization, protein expression studies in patient fibroblasts Annals of neurology Medium 22522442
2016 Deletion of the DnaJ domain of HSJ1b leads to loss of HSJ1b protein, increased cell death, protein aggregation, and enhanced autophagy. HSJ1b deficiency was also associated with significant reductions in tau and BDNF levels, suggesting the DnaJ domain is required for HSJ1b's role in maintaining proteostasis and preventing protein aggregation. Functional assays in cells carrying DnaJ domain deletion, protein expression analysis, cell death assays, autophagy markers Human mutation Medium 27449489
2025 DNAJB2 overexpression inhibits ERS marker proteins and the activated TLR2/Myd88/NF-κB pathway, reducing skin inflammation and angiogenesis in a rosacea model, linking DNAJB2 to endoplasmic reticulum stress-mediated inflammatory signaling. Overexpression in LL37-induced mouse rosacea model and cell lines, western blot for ERS markers and NF-κB pathway components, cytokine assays Inflammation Low 40035989
2025 A heterozygous DNAJB2 c.823+6C>T mutation reduces baseline DNAJB2 protein levels and impairs the upregulation of DNAJB2 in response to heat shock in patient fibroblasts. Cystamine treatment (150 μM, 48 h) increased DNAJB2 levels in both control and patient fibroblasts. Heat shock assay in patient-derived fibroblasts, western blot for DNAJB2 expression, cystamine pharmacological treatment Neurology international Low 40423229
2025 DNAJB2 (along with DNAJB6 and DNAJB8) prevents FG-rich nucleoporins (FG-Nups) from undergoing aberrant phase transitions, suggesting a role in nuclear pore complex quality control. Phase transition assays, co-expression experiments in cellular models bioRxivpreprint Low

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 HSJ1 is a neuronal shuttling factor for the sorting of chaperone clients to the proteasome. Current biology : CB 109 15936278
2012 A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation. Annals of neurology 64 22522442
2014 HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum. Neurology 45 25274842
2016 Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism. Human mutation 43 27449489
1996 Inhibition of hsc70-catalysed clathrin uncoating by HSJ1 proteins. The Biochemical journal 32 8870655
2010 DNAJB2 expression in normal and diseased human and mouse skeletal muscle. The American journal of pathology 24 20395441
2022 DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening. European journal of neurology 16 35286755
2021 PolyQ-expanded proteins impair cellular proteostasis of ataxin-3 through sequestering the co-chaperone HSJ1 into aggregates. Scientific reports 13 33837238
2017 Protein kinase CK2 modulates HSJ1 function through phosphorylation of the UIM2 domain. Human molecular genetics 11 28031292
2022 DNAJB2 c.184C>T mutation associated with distal hereditary motor neuropathy with rimmed vacuolar myopathy. Clinical neuropathology 10 35652544
2025 DNAJB2 Attenuates Rosacea Skin Inflammation and Angiogenesis by Inhibiting the Endoplasmic Reticulum Stress-mediated TLR2/Myd88/NF-κB pathway. Inflammation 2 40035989
2026 Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease. Journal of the peripheral nervous system : JPNS 1 41549766
2024 Clinical and genetic features of CMT2T in Italian patients confirm the importance of MME pathogenic variants in idiopathic, late-onset axonal neuropathies. Journal of the peripheral nervous system : JPNS 1 39251209
2026 Co-Existing Charcot-Marie-Tooth Disease Type II and Parkinson's Disease Linked to a Novel DNAjB2 Pathogenic Variant. Journal of central nervous system disease 0 41799927
2025 Impaired DNAJB2 Response to Heat Shock in Fibroblasts from a Neuropathy Patient with DNAJB2/HSJ1 Mutation: Cystamine as a Potential Therapeutic Intervention. Neurology international 0 40423229

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