DNAJB14

DNAJB14 is an endoplasmic reticulum-resident, single membrane-spanning Hsp40/J-protein co-chaperone that orients its J-domain toward the cytosol to recruit Hsc70/HSP70 to the ER membrane, thereby coupling cytosolic chaperone activity to ER membrane quality control (PMID:23018488). Through this activity it accelerates proteasome-dependent ERAD of misfolded transmembrane proteins such as CFTRΔF508 while sparing misfolded luminal substrates (PMID:23018488). Beyond degradation, DNAJB14 promotes the HSP70-independent tetrameric assembly of K+ channel subunits (hERG, Kv4.2) in the ER and rescues function of long-QT-associated hERG mutants by stabilizing them (PMID:27916661). It acts as a partner of the homologous co-chaperone DNAJB12, with which full-length DNAJB14 forms a complex that suppresses aggregation of ALS-associated mutant FUS and restores proteostasis in an HSP70-dependent manner, an activity lost by naturally occurring short isoforms (PMID:35082301). DNAJB14 and DNAJB12 are non-redundant, UPR-responsive co-chaperones that, together with SGTA, drive ER-to-cytosol protein reflux (ERCYS): binding HSC70 and SGTA via their cytosolic J-domains, they redistribute ER proteins such as PDI, PDIA4, and AGR2 to the cytosol during ER stress, where these proteins inhibit caspase-3 and wt-p53 to promote cancer cell survival and chemoresistance (PMID:37925033, PMID:40202782, PMID:41120732). Additional roles have been documented in HBV/HDV virion morphogenesis (PMID:41684842), PINK1/Drp1-linked mitochondrial dynamics under CCCP stress (PMID:37851175), and suppression of ferroptosis in retinal ganglion cells under ischemic injury (PMID:42202976).

1. 2012 High

   Established the foundational identity of DNAJB14 as an ER membrane co-chaperone, answering where it sits and what it does — orienting a cytosolic J-domain to recruit Hsc70 and drive ERAD of misfolded membrane proteins.

   Evidence Immunofluorescence, protease protection, co-IP, and overexpression degradation assays with proteasome inhibition in human cells

   PMID:23018488

   Open questions at the time

   • Selectivity for transmembrane over luminal substrates not mechanistically explained
   • Direct biochemical demonstration of substrate handoff to Hsc70 not shown
   • Endogenous (non-overexpression) contribution to ERAD not quantified
2. 2014 Medium

   Revealed that DNAJB14/DNAJB12 overexpression remodels ER/nuclear membranes into chaperone-dependent intranuclear structures (DJANGOS), establishing that its activity reshapes membrane architecture and requires functional DNAJ/Hsc70 chaperone activity.

   Evidence Fluorescence and electron microscopy, live imaging, genetic epistasis with chaperone-activity mutants in overexpressing cells

   PMID:24732912

   Open questions at the time

   • Phenomenon observed under overexpression; physiological relevance unclear
   • Functional consequence of DJANGOS for proteostasis not defined
3. 2016 High

   Demonstrated a chaperone-degradation-independent function: DNAJB14 promotes tetrameric assembly of K+ channels in the ER without HSP70, expanding its role from quality control to biogenesis and rescue of disease mutants.

   Evidence C. elegans and human cell genetic screening, in vitro tetrameric assembly assay, electrophysiology, oligomerization-defective control

   PMID:27916661

   Open questions at the time

   • Molecular basis for HSP70-independence not resolved
   • Whether assembly function generalizes beyond hERG/Kv4.2 unknown
4. 2022 High

   Identified the DNAJB14–DNAJB12 full-length complex as an HSP70-dependent suppressor of pathogenic protein aggregation, linking the co-chaperone pair to neurodegeneration-relevant proteostasis and showing isoform-dependent loss of this function.

   Evidence Reciprocal co-IP, aggregation assays and FRAP in cells and primary neurons, isoform comparison

   PMID:35082301

   Open questions at the time

   • How an ER membrane complex acts on cytosolic FUS aggregates mechanistically unclear
   • Stoichiometry of the DNAJB14/B12 complex not defined
5. 2023 Medium

   Connected DNAJB14 to UPR-induced ER-to-cytosol protein reflux and showed it is non-redundant with DNAJB12, while its own protein level is regulated by proteasomal degradation under reductive stress.

   Evidence siRNA knockdown, subcellular fractionation, UPR drug and proteasome inhibition, interactome analysis

   PMID:37925033

   Open questions at the time

   • Directionality and machinery of reflux translocation not fully defined
   • Structural basis of DUF1977 non-redundancy not tested functionally
6. 2023 Medium

   Extended DNAJB14 function to mitochondrial stress responses, showing it modulates PINK1 stabilization and Drp1 phosphorylation kinetics and influences mitochondrial morphology.

   Evidence Genetic knockout and overexpression, Western blot for PINK1 and phospho-Drp1, mitochondrial morphology imaging under CCCP

   PMID:37851175

   Open questions at the time

   • Direct molecular link between an ER co-chaperone and PINK1/Drp1 not established
   • Whether effect is direct or secondary to ER stress unknown
7. 2025 Medium

   Defined the mechanism of ERCYS at molecular resolution and its pro-survival output: DNAJB14/B12 bind HSC70 and SGTA via cytosolic J-domains to reflux PDIA4/AGR2 to the cytosol, where they inhibit caspase-3 and wt-p53, with J-domain mutations and silencing reversing the effect.

   Evidence Co-IP, J-domain mutagenesis, siRNA knockdown, fractionation, apoptosis/proliferation and drug-sensitivity assays

   PMID:40202782 PMID:41120732

   Open questions at the time

   • Physical transport route across the ER membrane during reflux not resolved
   • Generality of cytosolic-PDI-mediated p53/caspase inhibition across tumor types untested
8. 2025 Medium

   Distinguished DNAJB14 from DNAJB12 functionally in viral life cycles, showing DNAJB14 is selectively required for HBV virion morphogenesis and for production of infectious HDV.

   Evidence siRNA knockdown with virion/SVP secretion and HDV infectivity assays

   PMID:41684842

   Open questions at the time

   • The chaperone substrate(s) within the viral assembly pathway not identified
   • Whether the role depends on J-domain/Hsc70 activity not tested
9. 2026 Medium

   Linked DNAJB14 to ferroptosis suppression in retinal ganglion cells, showing protective gain-of-function and damaging loss-of-function in ischemic glaucoma models.

   Evidence Single-cell and bulk transcriptomics, gain/loss-of-function in murine glaucoma models, lipid peroxidation and mitochondrial function assays

   PMID:42202976

   Open questions at the time

   • Mechanism connecting the co-chaperone to lipid peroxidation control unknown
   • Whether protection requires its ER co-chaperone activity not tested

• How a single ER membrane co-chaperone mechanistically unifies ERAD, channel assembly, aggregation suppression, ER-to-cytosol reflux, viral morphogenesis, mitochondrial dynamics, and ferroptosis remains unresolved.
• No structural model of the DNAJB14/B12/HSC70/SGTA assembly
• The physical translocation mechanism underlying ERCYS is undefined
• Direct substrate repertoire of DNAJB14 versus DNAJB12 not comprehensively mapped