Affinage

DNAJC5

DnaJ homolog subfamily C member 5 · UniProt Q9H3Z4

Length
198 aa
Mass
22.1 kDa
Annotated
2026-06-09
24 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNAJC5/CSPα is a palmitoylated, membrane-associated HSC70 co-chaperone that operates in protein quality control by directing misfolded cytosolic proteins through the endo-lysosomal system (PMID:29531792, PMID:36626307). It serves as an essential mediator of misfolding-associated protein secretion (MAPS), chaperoning client proteins to the cell exterior downstream of the USP19 deubiquitinase and HSC70 (PMID:29531792). Palmitoylation, installed by multiple DHHC palmitoyl acyltransferases, anchors DNAJC5 on endosomal and Golgi-associated membranes and is required for its oligomerization and for secretion of clients including α-synuclein, with cytosolic α-synuclein being actively translocated into an endosomal compartment in a DNAJC5-dependent manner (PMID:36626307, PMID:41657026). DNAJC5 carries two coupled chaperoning activities: an endolysosomal pool drives ESCRT-dependent microautophagy, while a perinuclear pool dependent on the interactor SLC3A2/CD98hc mediates MAPS; uncoupling these processes generates autofluorescent storage material resembling NCL lipofuscin (PMID:35506243). The protein engages the synaptic machinery, interacting with HSC70, SNAP-25, and STXBP1/Munc18-1 (PMID:38193346), and is depalmitoylated by PPT1/CLN1, linking it biochemically to a second neuronal ceroid lipofuscinosis protein (PMID:26659577). DNAJC5 mutations (Leu115Arg, Leu116del) in the cysteine-string domain cause autosomal dominant neuronal ceroid lipofuscinosis (CLN4) through a gain of pathological function: the mutants oligomerize excessively, mislocalize from synaptic vesicles to prelysosomal compartments, deposit aggregates that directly damage lysosomal membranes, and drive lipofuscinosis and neurodegeneration, whereas knockout animals show no such pathology (PMID:31663851, PMID:40855364, PMID:40397740). The ubiquitin ligase CHIP acts as a protective microautophagy regulator that ubiquitinates and clears these aggregates (PMID:40855364). Beyond its neuronal role, DNAJC5 has been implicated in cancer-cell contexts via SKP2/p27 and EGFR/AP2A1 trafficking (PMID:33662413, PMID:40374748).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2011 Medium

    Establishing the disease relevance of the cysteine-string domain showed that CLN4 mutations act by perturbing palmitoylation-dependent membrane targeting rather than by simple loss of expression.

    Evidence Exome/candidate-gene sequencing plus palmitoylation-dependent sorting assays in neuronal cells with two independent mutations

    PMID:21820099

    Open questions at the time
    • Did not establish whether reduced CSPα was cause or consequence
    • No in vivo demonstration of pathogenic mechanism
    • Did not resolve gain- vs loss-of-function
  2. 2015 High

    Identifying CSPα as a PPT1/CLN1 depalmitoylation substrate connected two NCL disease proteins biochemically and placed DNAJC5 within a palmitoylation cycle at synaptic and lysosomal membranes.

    Evidence In vitro depalmitoylation assays and quantitative palmitoyl-proteomics of patient versus control brain

    PMID:26659577

    Open questions at the time
    • Did not define the DHHC enzymes installing the modification
    • Functional consequence of the palmitoylation cycle for chaperone activity not resolved
  3. 2018 High

    Defining DNAJC5 as an essential mediator of MAPS revealed a function for the protein in unconventional secretion of misfolded cytosolic clients and placed USP19 and HSC70 upstream in the pathway.

    Evidence Reciprocal Co-IP, knockdown/knockout secretion assays with defined clients, subcellular fractionation

    PMID:29531792

    Open questions at the time
    • Mechanism of client translocation across membranes not defined
    • Did not establish palmitoylation requirement
    • Physiological clients in neurons not enumerated
  4. 2019 High

    Demonstrating that CLN4 mutants oligomerize excessively and mislocalize to prelysosomal compartments, with phenotypes attenuated by reducing wild-type CSPα or Hsc70 dosage, established a dominant hypermorphic gain-of-function mechanism.

    Evidence Drosophila transgenic models, immunofluorescence co-localization, genetic dosage epistasis, ultrastructural analysis

    PMID:31663851

    Open questions at the time
    • Did not identify the lysosomal damage mechanism
    • Mammalian validation absent
    • Clearance pathways for aggregates unknown
  5. 2021 Medium

    Linking DNAJC5 to SKP2-mediated p27 degradation extended its functional repertoire to cell-cycle control in hepatocellular carcinoma, beyond the canonical neuronal context.

    Evidence Co-IP, overexpression/knockdown, cell-cycle flow cytometry in HCC cells

    PMID:33662413

    Open questions at the time
    • Single lab, cancer-specific context
    • Mechanism connecting chaperone activity to SKP2 not resolved
    • No in vivo tumor confirmation
  6. 2022 High

    Resolving DNAJC5 into two coupled activities — endolysosomal microautophagy and SLC3A2-dependent perinuclear MAPS — showed how uncoupling the pathways produces NCL-like autofluorescent storage material and neurodegeneration.

    Evidence Proximity labeling/BioID, Co-IP, shRNA/KO, microscopy, ESCRT perturbation, Drosophila neurodegeneration model

    PMID:35506243

    Open questions at the time
    • Molecular basis of SLC3A2-dependent perinuclear targeting not defined
    • How the two pools interconvert unknown
  7. 2023 High

    Showing that palmitoylation-driven DNAJC5 oligomerization on endosomal membranes drives α-synuclein translocation and secretion provided a mechanistic basis for the secretory function and its disease relevance.

    Evidence HEK293T reconstitution, palmitoylation-deficient mutants, endosomal translocation and rescue assays, validation in SH-SY5Y and iPSC dopamine neurons

    PMID:36626307

    Open questions at the time
    • Structure of the active oligomer not determined
    • Physiological vs pathological balance of α-syn secretion unresolved
  8. 2024 Medium

    Mapping the DNAJC5 interactome in neuroendocrine cells confirmed Hsc70 and SNAP-25 binding, identified STXBP1/Munc18-1 as a partner, and showed the L115R mutation selectively disrupts SNAP-25 and STXBP1 interactions while sparing Hsc70.

    Evidence miniTurbo proximity labeling in PC12 cells, LC-MS proteomics, western blot validation

    PMID:38193346

    Open questions at the time
    • Functional consequence of lost SNAP-25/STXBP1 interactions not tested
    • Single cell type
  9. 2025 High

    Identifying direct lysosomal membrane damage by CLN4 aggregates and CHIP as a protective microautophagy regulator defined both the proximate cytotoxic event and a clearance mechanism that rescues lysosomal function in vivo.

    Evidence iPSC i3Neurons with CLN4 mutations, in vitro membrane damage assay, genome-wide CRISPR screen, organelle proteomics, Drosophila model

    PMID:40855364

    Open questions at the time
    • Mechanism of physical membrane permeabilization not fully resolved
    • Whether CHIP modulation is therapeutically tractable unknown
  10. 2025 High

    Transgenic mouse modeling settled the gain- versus loss-of-function question, showing CLN4 mutant overexpression causes lipofuscinosis and GRODs while knockouts do not.

    Evidence Thy1-promoter WT and mutant CSPα transgenic lines, conventional and conditional knockouts, neuropathology and behavior

    PMID:40397740

    Open questions at the time
    • Does not address normal physiological role lost in knockouts
    • Cell-type specificity of vulnerability incompletely mapped
  11. 2025 Medium

    Implicating DNAJC5 in misfolded protein secretion during cellular senescence extended the MAPS function to proteotoxic stress and additional clients such as TDP-43.

    Evidence Transcriptomics/proteomics and DNAJC5 knockdown secretion assays in senescent cells (preprint)

    PMID:bio_10.1101_2025.09.07.674107

    Open questions at the time
    • Preprint, not peer-reviewed
    • Single lab
    • Mechanistic detail of TDP-43 secretion not resolved
  12. 2026 High

    Defining DHHC enzymes as the palmitoylating machinery and mapping a minimal DC95 module sufficient for palmitoylation, Golgi translocation, and secretion completed the upstream control logic of DNAJC5 membrane targeting.

    Evidence Palmitoylation assays with DHHC panel, subcellular fractionation/IF, deletion mutagenesis, secretion assays in human cells

    PMID:41657026

    Open questions at the time
    • Which DHHC enzyme acts physiologically in neurons unresolved
    • Relationship between Golgi and endosomal pools not defined
  13. 2026 Medium

    Identifying TDP43 and hnRNP K as regulators of DNAJC5 pre-mRNA splicing introduced an upstream RNA-level control layer that links DNAJC5 abundance to RNA-binding proteins implicated in neurodegeneration.

    Evidence siRNA knockdown, RNA immunoprecipitation, RT-PCR splicing assays with internal binding-site mutagenesis

    PMID:41983529

    Open questions at the time
    • Functional impact of aberrant isoforms on trafficking not quantified
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of the palmitoylated DNAJC5 oligomer and how it physically translocates clients across or permeabilizes lysosomal membranes remains undefined.
  • No high-resolution structure of the functional oligomer
  • Mechanism of membrane translocation/permeabilization unresolved
  • Native physiological MAPS clients in healthy neurons not enumerated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 3 GO:0008289 lipid binding 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005764 lysosome 3 GO:0005768 endosome 3 GO:0005794 Golgi apparatus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-9609507 Protein localization 2 R-HSA-9612973 Autophagy 2
Partners
CHIPEGFRHSPA8SKP2SLC3A2SNAP25STXBP1USP19

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Disease-causing mutations p.Leu116del and p.Leu115Arg in the cysteine-string domain of DNAJC5/CSPα affect palmitoylation-dependent sorting and reduce the amount of CSPα in neuronal cells, implying the cysteine-string domain is required for proper membrane targeting. Exome sequencing, candidate-gene sequencing, and cell-based assays of palmitoylation-dependent sorting in neuronal cells American journal of human genetics Medium 21820099
2015 DNAJC5/CSPα is a substrate of the depalmitoylating enzyme PPT1/CLN1; in DNAJC5/CLN4 patient brains PPT1 is massively increased, mis-localized, and has dramatically reduced specific enzymatic activity, establishing a biochemical link between two NCL disease proteins and revealing global changes in protein palmitoylation at synaptic and lysosomal proteins. Biochemical fractionation, enzymatic activity assays, quantitative palmitoyl-proteomics (palmitome mass spectrometry) of patient versus control brain tissue Acta neuropathologica High 26659577
2018 DNAJC5 acts as an essential mediator of misfolding-associated protein secretion (MAPS), a pathway for unconventional secretion of misfolded cytosolic proteins. USP19 deubiquitinase binds HSC70 and acts upstream of HSC70 and DNAJC5. As a membrane-associated protein preferentially localized to late endosomes/lysosomes, DNAJC5 chaperones MAPS client proteins to the cell exterior; secreted misfolded proteins can be endocytosed and degraded in recipient-cell lysosomes. Co-immunoprecipitation, knockdown/knockout cellular assays, subcellular fractionation, secretion assays with defined client proteins Cell discovery High 29531792
2019 CLN4 mutations in DNAJC5/CSPα drive excessive oligomerization and mislocalization of CSPα from synaptic vesicles to prelysosomal (HRS/LAMP1-positive) compartments in Drosophila neurons. Reducing endogenous wild-type dCSP or Hsc70 gene dosage attenuates CLN4 phenotypes (lethality, oligomerization, prelysosomal accumulation), establishing a dominant hypermorphic gain-of-function mechanism requiring wild-type CSPα and Hsc70. Drosophila transgenic models, immunofluorescence co-localization, genetic epistasis (dosage reduction of dCSP and Hsc70), ultrastructural analysis eLife High 31663851
2022 DNAJC5 has two functionally distinct but coupled chaperoning activities: endolysosome-associated DNAJC5 promotes ESCRT-dependent microautophagy, while a perinuclear non-lysosomal pool mediates MAPS. The interactor SLC3A2/CD98hc is essential for perinuclear DNAJC5 localization and MAPS but dispensable for microautophagy. Uncoupling these two processes (by loss of SLC3A2 or expression of ANCL mutants) generates DNAJC5-containing autofluorescent storage materials resembling NCL lipofuscin and induces neurodegeneration in a Drosophila model. Functional proteomics (proximity labeling/BioID), Co-IP, shRNA knockdown/KO, fluorescence microscopy, Drosophila neurodegeneration model, ESCRT perturbation assays Autophagy High 35506243
2023 DNAJC5 undergoes palmitoylation and anchors on endosomal membranes; palmitoylation is essential for DNAJC5-induced α-synuclein secretion. Cytosolic α-syn is actively translocated into an endosomal membrane compartment in a DNAJC5-dependent manner. A palmitoylation-deficient mutation reduces α-syn secretion, which can be rescued by a membrane-targeting peptide that forces DNAJC5 oligomerization, indicating that palmitoylated DNAJC5 oligomers drive α-syn unconventional secretion. Reconstitution in HEK293T cells, palmitoylation-deficient mutants, membrane fractionation, endosomal translocation assays, rescue with membrane-targeting peptide, validation in SH-SY5Y neurons and iPSC-derived midbrain dopamine neurons eLife High 36626307
2021 DNAJC5 interacts with SKP2 and enhances SKP2-mediated degradation of the cyclin-dependent kinase inhibitor p27, promoting G1-to-S cell-cycle progression in hepatocellular carcinoma cells; DNAJC5 knockdown rescues p27 protein levels. Co-immunoprecipitation, overexpression/knockdown, cell-cycle flow cytometry, western blotting Biochimica et biophysica acta. Molecular cell research Medium 33662413
2024 Proximity labeling in PC12 neuroendocrine cells confirmed DNAJC5 interacts with Hsc70 and SNAP-25, and identified STXBP1/Munc18-1 as a novel DNAJC5-binding protein. The ANCL mutation L115R inhibits interactions with SNAP-25 and STXBP1/Munc18-1 but does not affect Hsc70 binding, mapping which interactions are disrupted by disease mutation. Proximity labeling (miniTurbo) in stable PC12 cell lines, LC-MS proteomics, western blot validation The Biochemical journal Medium 38193346
2025 CLN4-linked DNAJC5 mutant aggregates on lysosomal membranes cause direct lysosomal membrane damage in iPSC-derived neurons (established by in vitro membrane-damaging assay). The ubiquitin ligase CHIP acts as a central microautophagy regulator that ubiquitinates CLN4 aggregates to protect lysosomes; ectopic CHIP improves lysosomal function in CLN4 neurons and alleviates lipofuscin accumulation and neurodegeneration in a Drosophila CLN4 model. iPSC-derived neurons (i3Neuron) with DNAJC5 CLN4 mutations, in vitro lysosome membrane damage assay, genome-wide CRISPR screen, organelle-specific proteomics, Drosophila in vivo model Nature cell biology High 40855364
2025 Mice overexpressing CLN4 mutant (Leu115Arg or Leu116Δ) CSPα develop motor deficits and neuronal lipofuscinosis with GROD-like structures, whereas conventional or conditional DNAJC5 knockout mice show no lipofuscinosis or GRODs, establishing that DNAJC5 mutations cause neuronal lipofuscinosis through a cell-autonomous gain of pathological function, not loss of function. Transgenic mouse lines (Thy1-promoter WT, Leu115Arg, Leu116Δ CSPα), conventional and conditional knockout mice, neuropathological analysis, behavioral testing Science advances High 40397740
2026 DNAJC5 is palmitoylated by multiple DHHC palmitoyl acyltransferases in human cells; DHHC11 overexpression enriches DNAJC5 in a Golgi-associated compartment and increases unconventional protein secretion. Mutagenesis defined a minimal module (DC95: CS domain plus C-terminal 62 residues and short upstream segment) sufficient for palmitoylation, Golgi translocation, and secretion; deletion of 5 residues from DC95 abolishes all three activities. Palmitoylation assays with DHHC enzyme panel, subcellular fractionation/immunofluorescence, deletion mutagenesis, secretion assays in human cells Traffic (Copenhagen, Denmark) High 41657026
2025 Misfolded protein secretion in senescent human cells requires DNAJC5; the vesicle-associated HSP70 co-chaperone DNAJC5 mediates expulsion of misfolded proteins (including TDP-43) through the endo-lysosomal system during proteotoxic stress in senescent cells. Multi-dimensional transcriptomics and proteomics, knockdown of DNAJC5 in senescent human cells, secretion assays under proteotoxic stress bioRxivpreprint Medium bio_10.1101_2025.09.07.674107
2025 DNAJC5 interacts with the intracellular domain of EGFR and with the endocytosis adaptor AP2A1; DNAJC5 overexpression enhances EGFR endocytosis and recycling, augmenting downstream EGFR signaling. AP2A1 knockdown attenuates DNAJC5-driven EGFR trafficking and lung adenocarcinoma cell proliferation/migration. Co-immunoprecipitation, overexpression/knockdown in LUAD cell lines, in vitro and in vivo proliferation/migration assays, EGFR trafficking assays Communications biology Medium 40374748
2026 TDP43 and hnRNP K regulate canonical splicing of DNAJC5 pre-mRNA; their interaction is RNA-dependent, and DNAJC5 canonical splicing depends on internal TDP43 and hnRNP K binding sites. Loss of either factor introduces aberrant splicing of DNAJC5, affecting its role in endosomal trafficking. siRNA knockdown of TDP43 and hnRNP K, RNA immunoprecipitation, RT-PCR splicing assays, RNA-dependency of protein interaction assays Cell biology international Medium 41983529

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. American journal of human genetics 214 21820099
2011 Exome-sequencing confirms DNAJC5 mutations as cause of adult neuronal ceroid-lipofuscinosis. PloS one 98 22073189
2018 DNAJC5 facilitates USP19-dependent unconventional secretion of misfolded cytosolic proteins. Cell discovery 88 29531792
2015 Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation. Acta neuropathologica 69 26659577
2012 Mutations in the gene DNAJC5 cause autosomal dominant Kufs disease in a proportion of cases: study of the Parry family and 8 other families. PloS one 67 22235333
2012 Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease. Clinical genetics 51 22978711
2023 Unconventional secretion of α-synuclein mediated by palmitoylated DNAJC5 oligomers. eLife 44 36626307
2014 Caenorhabditis elegans dnj-14, the orthologue of the DNAJC5 gene mutated in adult onset neuronal ceroid lipofuscinosis, provides a new platform for neuroprotective drug screening and identifies a SIR-2.1-independent action of resveratrol. Human molecular genetics 42 24947438
2022 Abnormal triaging of misfolded proteins by adult neuronal ceroid lipofuscinosis-associated DNAJC5/CSPα mutants causes lipofuscin accumulation. Autophagy 38 35506243
2021 DNAJC5 promotes hepatocellular carcinoma cells proliferation though regulating SKP2 mediated p27 degradation. Biochimica et biophysica acta. Molecular cell research 19 33662413
2019 A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism. eLife 16 31663851
2020 Autosomal-dominant adult neuronal ceroid lipofuscinosis caused by duplication in DNAJC5 initially missed by Sanger and whole-exome sequencing. European journal of human genetics : EJHG 14 31919451
2022 Adult-Onset Neuronal Ceroid Lipofuscinosis With a Novel DNAJC5 Mutation Exhibits Aberrant Protein Palmitoylation. Frontiers in aging neuroscience 12 35462699
2022 Safeguarding Lysosomal Homeostasis by DNAJC5/CSPα-Mediated Unconventional Protein Secretion and Endosomal Microautophagy. Frontiers in cell and developmental biology 11 35620055
2024 Proximity labelling reveals effects of disease-causing mutation on the DNAJC5/cysteine string protein α interactome. The Biochemical journal 6 38193346
2025 Neuronal lipofuscinosis caused by Kufs disease/CLN4 DNAJC5 mutations but not by a CSPα/DNAJC5 deficiency. Science advances 2 40397740
2025 CHIP protects lysosomes from CLN4 mutant-induced membrane damage. Nature cell biology 2 40855364
2024 LINC00624 affects hepatocellular carcinoma proliferation and apoptosis through the miR-342-3p/DNAJC5 axis. Journal of biochemical and molecular toxicology 2 38348704
2025 DNAJC5 facilitates the proliferation and migration of lung adenocarcinoma cells by augmenting EGFR trafficking. Communications biology 1 40374748
2021 Early-Onset Vascular Dementia in a 43-Year-Old Man with Accelerated Atherosclerotic Disease, Elevated Lipoprotein (a), and a Missense DNAJC5 Variant with Potential Association to Adult-Onset Ceroid Lipofuscinosis. Case reports in neurology 1 34720963
2026 Palmitoyl Acyltransferases Control the Membrane Localization of DNAJC5 to Regulate Unconventional Protein Secretion. Traffic (Copenhagen, Denmark) 0 41657026
2026 TDP43 and hnRNP K Regulate Alternative Splicing of DNAJC5. Cell biology international 0 41983529
2025 DNAJC5 promotes cisplatin resistance in epithelial ovarian cancer by autophagy induced by the BiP/IRE1α/XBP1 endoplasmic reticulum stress pathway. Scientific reports 0 41038875
2024 Tissue distribution of cysteine string protein/DNAJC5 in C. elegans analysed by CRISPR/Cas9-mediated tagging of endogenous DNJ-14. Cell and tissue research 0 38403745

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