DNAJB2 Gene: Function, Mutations, and Role in Neurodegenerative Diseases

DNAJB2 (DnaJ heat shock protein family (Hsp40) member B2) encodes a member of the DnaJ/Hsp40 family of cochaperones. The protein contains a conserved J domain that interacts with Hsp70 chaperones, stimulating their ATPase activity. DNAJB2 is involved in protein folding, quality control, and targeting of misfolded proteins for degradation via the ubiquitin-proteasome system. It is highly expressed in the nervous system and plays a critical role in neuronal survival. Mutations in DNAJB2 are associated with autosomal recessive distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2T (CMT2T).

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Protein processing in endoplasmic reticulum (KEGG: hsa04141)

• Ubiquitin mediated proteolysis (KEGG: hsa04120)

• Chaperone-mediated autophagy

• HSF1-dependent transactivation

DNAJB2 (HSJ1) is a 277-amino acid protein (isoform a) with an N-terminal J domain, a glycine/phenylalanine-rich region, and a C-terminal domain containing a ubiquitin-interacting motif (UIM). It functions as a cochaperone for Hsp70, enhancing ATP hydrolysis and substrate binding. The UIM allows DNAJB2 to bind ubiquitinated proteins, targeting them for proteasomal degradation. Two major isoforms exist: isoform a (full-length) and isoform b (lacking the UIM). DNAJB2 is predominantly cytosolic but can shuttle to the nucleus under stress. It is essential for neuronal homeostasis and protection against proteotoxic stress.