Disease relevance of DNAJC3

• We previously found that influenza virus avoids the translational inhibitory effects of activated PKR by activating a cellular inhibitory protein, termed P58IPK, based on its Mr of 58,000 [1].
• P58, expressed as a histidine fusion protein in Escherichia coli, blocked both the autophosphorylation of PKR and phosphorylation of the alpha subunit of eIF-2 [2].

High impact information on DNAJC3

• (iii) Purified, recombinant hsp40 protein inhibited P58IPK in an identical in vitro assay [1].
• Regulation of interferon-induced protein kinase PKR: modulation of P58IPK inhibitory function by a novel protein, P52rIPK [3].
• Double-stranded RNA-independent dimerization of interferon-induced protein kinase PKR and inhibition of dimerization by the cellular P58IPK inhibitor [4].
• We demonstrated, utilizing both the yeast and lambda systems, that P58IPK, a member of the tetratricopeptide repeat protein family, can block kinase activity by preventing PKR dimerization [4].
• Computer analysis revealed that P58 contains regions of homology to the DnaJ family of proteins and a much lesser degree of similarity to the PKR natural substrate, eIF-2 alpha [2].

Biological context of DNAJC3

• The P58 protein inhibits both the autophosphorylation of PKR and the phosphorylation of the PKR natural substrate, the alpha subunit of eukaryotic initiation factor eIF-2 [5].
• Chromosomal assignment of the gene encoding the human 58-kDa inhibitor (PRKRI) of the interferon-induced dsRNA-activated protein kinase to chromosome 13q32 [6].
• Using fluorescence in situ hybridization, we have mapped the p58 gene (PRKRI) to human chromosome 13 band q32 [6].
• Curiously, PKR aa 244 to 296 contain the binding site for a select group of specific inhibitors, including the cellular protein P58IPK [4].

Anatomical context of DNAJC3

• P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling [7].

Physical interactions of DNAJC3

• Utilizing experimental approaches, which included coprecipitation or coselection of native and recombinant wild-type and mutant proteins, we found that P58 can efficiently complex with the PKR protein kinase [5].
• (iv) Finally, we demonstrate that hsp40 directly complexes with P58IPK, in vitro, suggesting the inhibition occurs through a direct interaction [1].

Regulatory relationships of DNAJC3

• These data, taken together, demonstrate that P58 inhibits PKR through a direct interaction, which is likely independent of the binding of double-stranded RNA to the protein kinase [5].
• P52rIPK regulates the molecular cochaperone P58IPK to mediate control of the RNA-dependent protein kinase in response to cytoplasmic stress [8].

Other interactions of DNAJC3

• P52rIPK and P58IPK interacted in a yeast two-hybrid assay and were recovered as a complex from mammalian cell extracts [3].
• Like many protein kinases, PKR is regulated through direct interactions with activator and inhibitory molecules, including P58IPK, a cellular PKR inhibitor [3].
• The DnaJ sequences, present at the carboxyl terminus of P58, were dispensable for binding in vitro, while sequences containing the eIF-2 alpha similarity region were essential for efficient complex formation [5].

Analytical, diagnostic and therapeutic context of DNAJC3

• Sequence analysis revealed that P58 is a member of the tetratricopeptide family of proteins [5].
• Western blot (immunoblot) analysis showed that P58 is present not only in bovine cells but also in human, monkey, and mouse cells, suggesting the protein is highly conserved [2].

References