The protein encoded by this gene contains multiple tetratricopeptide repeat (TPR) motifs as well as the highly conserved J domain found in DNAJ chaperone family members. It is a member of the tetratricopeptide repeat family of proteins and acts as an inhibitor of the interferon-induced, dsRNA-activated protein kinase (PKR).[3]
Clinical significance
The DNAJC3 protein is an important apoptotic constituent. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[4] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
Moreover, an important role for DNAJC3 has been attributed to diabetes mellitus as well as multi system neurodegeneration.[5][6]Diabetes mellitus and neurodegeneration are common diseases for which shared genetic factors are still only partly known. It was shown that loss of the BiP (immunoglobulin heavy-chain binding protein) co-chaperone DNAJC3 leads to diabetes mellitus and widespread neurodegeneration. Accordingly, three siblings were investigated with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy. Subsequently, exome sequencing identified 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. DNAJC3 was absent in fibroblasts from all affected subjects in both families. To delineate the phenotypic and mutational spectrum and the genetic variability of DNAJC3, 8,603 exomes were further analyzed, including 506 from families affected by diabetes, ataxia, upper-motor-neuron damage, peripheral neuropathy, or hearing loss. This analysis revealed only one further loss-of-function allele in DNAJC3 and no further associations in subjects with only a subset of the features of the main phenotype.[5] Notably, the DNAJC3 protein is also considered as an important marker for stress in the endoplasmatic reticulum.
[6]
↑Polyak SJ, Tang N, Wambach M, Barber GN, Katze MG (Jan 1996). "The P58 cellular inhibitor complexes with the interferon-induced, double-stranded RNA-dependent protein kinase, PKR, to regulate its autophosphorylation and activity". The Journal of Biological Chemistry. 271 (3): 1702–7. doi:10.1074/jbc.271.3.1702. PMID8576172.
Polyak SJ, Tang N, Wambach M, Barber GN, Katze MG (Jan 1996). "The P58 cellular inhibitor complexes with the interferon-induced, double-stranded RNA-dependent protein kinase, PKR, to regulate its autophosphorylation and activity". The Journal of Biological Chemistry. 271 (3): 1702–7. doi:10.1074/jbc.271.3.1702. PMID8576172.
Korth MJ, Lyons CN, Wambach M, Katze MG (May 1996). "Cloning, expression, and cellular localization of the oncogenic 58-kDa inhibitor of the RNA-activated human and mouse protein kinase". Gene. 170 (2): 181–8. doi:10.1016/0378-1119(95)00883-7. PMID8666242.
Korth MJ, Edelhoff S, Disteche CM, Katze MG (Jan 1996). "Chromosomal assignment of the gene encoding the human 58-kDa inhibitor (PRKRI) of the interferon-induced dsRNA-activated protein kinase to chromosome 13q32". Genomics. 31 (2): 238–9. doi:10.1006/geno.1996.0038. PMID8824808.
Melville MW, Tan SL, Wambach M, Song J, Morimoto RI, Katze MG (Feb 1999). "The cellular inhibitor of the PKR protein kinase, P58(IPK), is an influenza virus-activated co-chaperone that modulates heat shock protein 70 activity". The Journal of Biological Chemistry. 274 (6): 3797–803. doi:10.1074/jbc.274.6.3797. PMID9920933.
Horng T, Barton GM, Medzhitov R (Sep 2001). "TIRAP: an adapter molecule in the Toll signaling pathway". Nature Immunology. 2 (9): 835–41. doi:10.1038/ni0901-835. PMID11526399.
Yan W, Gale MJ, Tan SL, Katze MG (Apr 2002). "Inactivation of the PKR protein kinase and stimulation of mRNA translation by the cellular co-chaperone P58(IPK) does not require J domain function". Biochemistry. 41 (15): 4938–45. doi:10.1021/bi0121499. PMID11939789.
Ladiges W, Morton J, Hopkins H, Wilson R, Filley G, Ware C, Gale M (Mar 2002). "Expression of human PKR protein kinase in transgenic mice". Journal of Interferon & Cytokine Research. 22 (3): 329–34. doi:10.1089/107999002753675758. PMID12034040.
van Huizen R, Martindale JL, Gorospe M, Holbrook NJ (May 2003). "P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling". The Journal of Biological Chemistry. 278 (18): 15558–64. doi:10.1074/jbc.M212074200. PMID12601012.