What is DNAJB9 (ERdj4) protein?

DNAJB9 Protein: Identity and Clinical Significance

Molecular Identity and Function

DNAJB9 (DnaJ homolog subfamily B member 9), also known as ERdj4, MDG1, or MDJ7, is an endoplasmic reticulum (ER)-resident co-chaperone protein that works with the heat shock protein BiP (Hsp70) to regulate protein folding and cellular stress responses. 1

• DNAJB9 contains a highly conserved J-domain that stimulates BiP's ATPase activity, providing energy for protein refolding or targeting misfolded proteins for degradation 1
• The protein regulates lipogenesis and protein synthesis by promoting degradation of SREBP1c and assembly of the mTORC2 protein complex 1
• DNAJB9 controls epithelial-to-mesenchymal transition, a process critical during embryogenesis, wound healing, and tumor development 1
• The protein promotes cellular survival in stressed cells and may improve engraftment of transplanted human stem cells 1

Critical Diagnostic Role in Fibrillary Glomerulonephritis

DNAJB9 serves as a highly specific and sensitive diagnostic biomarker for fibrillary glomerulonephritis (FGN), with 98-100% sensitivity and >99-100% specificity, revolutionizing the diagnosis of this rare kidney disease. 2, 3

Diagnostic Performance

• DNAJB9 immunohistochemistry shows strong, homogeneous, smudgy staining of glomerular deposits in FGN cases 2
• The protein was detected in all FGN patients but not in healthy glomeruli or in 19 types of non-FGN glomerular diseases 3
• DNAJB9 represents the fourth most abundant protein in FGN glomeruli, with >6-fold overexpression compared to amyloidosis glomeruli 3
• Immunoelectron microscopy demonstrates DNAJB9 localization specifically to FGN fibrils (12-24 nm diameter), but not to amyloid fibrils or immunotactoid glomerulopathy microtubules 2

Clinical Application in Kidney Biopsy Evaluation

• The KDIGO 2021 guidelines explicitly list DNAJB9 as a target antigen to detect during kidney biopsy evaluation, alongside PLA2R and THSD7A 4
• DNAJB9 immunohistochemistry allows rapid and accurate FGN diagnosis without requiring electron microscopy, though EM remains useful for confirming fibril morphology 2, 5
• High DNAJB9 plasma levels are specific for FGN and serve as a diagnostic marker 1
• In diffuse and global disorders like membranous glomerulonephritis, even a portion of a single glomerulus may be adequate for DNAJB9 detection 4

Pathogenic Implications

• DNAJB9 co-deposits with IgG-γ in FGN glomeruli, suggesting either a role as a putative antigen or secondary binding to misfolded IgG 3, 5
• The magnitude and specificity of DNAJB9 overabundance suggests this protein plays a role in FGN pathogenesis, possibly through unfolded protein response pathways 3, 6
• Sanger sequencing shows the deposited DNAJB9 protein does not have major sequence or structural alterations 3

Important Clinical Caveats

• Two FGN cases that did not stain for DNAJB9 were unique, having glomerular staining for IgG only (without κ or λ light chains) on immunofluorescence 2
• Very focal DNAJB9 staining was observed in one case of smoking-related glomerulopathy, representing the only false-positive among non-FGN diseases 2
• FGN remains a disease with poor prognosis—50% of patients require dialysis within 2 years of diagnosis—though transplantation outcomes are favorable with only 20% recurrence rate 5