DnaJ heat shock protein family member C3 (DNAJC3)

DnaJ heat shock protein family member C3 (DNAJC3) is an endoplasmic reticulum-resident co-chaperone of the Hsp40 (DNAJ) family that contains multiple tetratricopeptide repeat (TPR) motifs and a highly conserved J domain[2][3]. It acts as an essential negative regulator in the unfolded protein response (UPR) during ER stress, binding to and inhibiting the eIF2α kinases PKR, PERK, and GCN2, thereby reducing eIF2α phosphorylation and moderating cellular stress responses[2][3]. DNAJC3 helps preserve pancreatic β-cell survival under ER stress and is crucial for normal protein folding and apoptosis regulation. Pathogenic mutations cause syndromic forms of diabetes, often associated with multisystem neurodegeneration and hearing loss, while its upregulation or dysfunction is central in ER stress-related pathologies such as diabetes and certain degenerative diseases[1][3]. No clinically approved drugs currently act directly on DNAJC3.

Other names

P58IPKERdj6PRKRIProtein kinase inhibitor of 58 kDaInterferon-induced, double-stranded RNA-activated protein kinase inhibitorEndoplasmic reticulum DNA J domain-containing protein 6DnaJ (Hsp40) homolog, subfamily C, member 3Protein kinase inhibitor p58HP58

Inhibits PKR and other eIF2α kinases to prevent excessive inhibition of protein synthesis during ER stress[2][3]. Acts as a negative feedback modulator in the UPR to reduce ER stress-induced apoptosis in β-cells[1][2]. Functions as a co-chaperone with BiP/HSPA5 and HSC70, stimulating their ATPase activity[2].