DNAJC3

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Description

The DNAJC3 (DnaJ heat shock protein family (Hsp40) member C3) is a protein-coding gene located on chromosome 13.

DNAJC3, also known as DnaJ homolog subfamily C member 3, is a protein encoded by the DNAJC3 gene in humans. It contains multiple tetratricopeptide repeat (TPR) motifs and the highly conserved J domain found in DNAJ chaperone family members. DNAJC3 is a member of the tetratricopeptide repeat family of proteins and acts as an inhibitor of the interferon-induced, dsRNA-activated protein kinase (PKR). Loss of DNAJC3 has been linked to diabetes mellitus and multi-system neurodegeneration. Studies have shown that loss of DNAJC3 leads to diabetes mellitus and widespread neurodegeneration, suggesting a crucial role for this protein in maintaining cellular homeostasis. Three siblings with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy, were found to carry a homozygous stop mutation in DNAJC3. Further screening of a diabetes database with 226,194 individuals yielded eight phenotypically similar individuals and one family carrying a homozygous DNAJC3 deletion, highlighting the clinical significance of DNAJC3 in human health.

DNAJC3 plays a critical role in the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. It acts as a negative regulator of EIF2AK4/GCN2 kinase activity by preventing the phosphorylation of eIF-2-alpha at 'Ser-52', effectively attenuating general protein synthesis under ER stress, hypothermic and amino acid starving stress conditions. As a co-chaperone of HSPA8/HSC70, DNAJC3 stimulates its ATPase activity. Additionally, it may inhibit both the autophosphorylation of EIF2AK2/PKR and its ability to catalyze phosphorylation of EIF2A. DNAJC3 may also inhibit EIF2AK3/PERK activity. It interacts with EIF2AK4/GCN2, EIF2AK3, and EIF2AK2, forming a trimeric complex with DNAJB1 and HSPA8. This interaction occurs under ER stress, hypothermic and amino acid starving stress conditions and inhibits EIF2AK4/GCN2 kinase activity.

DNAJC3 is also known as ACPHD, ERdj6, HP58, P58, P58IPK, PRKRI, p58(IPK).

Associated Diseases

• Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus
• Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome