DNAJC3 explained

DnaJ homolog subfamily C member 3 is a protein that in humans is encoded by the DNAJC3 gene.^{[1] [2]}

Function

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

An important role for DNAJC3 has been attributed to diabetes mellitus as well as multi system neurodegeneration.^{[4] [5]} 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.^[4] Notably, the DNAJC3 protein is also considered as an important marker for stress in the endoplasmatic reticulum. ^[5]

Interactions

DNAJC3 has been shown to interact with:

• EIF2AK2,^{[6] [7]}
• EIF2AK3,^[8] and
• PRKRIR.^[7]

Further reading

• Polyak SJ, Tang N, Wambach M, Barber GN, Katze MG . 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 . Jan 1996 . 8576172 . 10.1074/jbc.271.3.1702 . free .
• Korth MJ, Lyons CN, Wambach M, Katze MG . 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 . May 1996 . 8666242 . 10.1016/0378-1119(95)00883-7 .
• Korth MJ, Edelhoff S, Disteche CM, Katze MG . 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 . Jan 1996 . 8824808 . 10.1006/geno.1996.0038 .
• Gale M, Blakely CM, Hopkins DA, Melville MW, Wambach M, Romano PR, Katze MG . Regulation of interferon-induced protein kinase PKR: modulation of P58IPK inhibitory function by a novel protein, P52rIPK . Molecular and Cellular Biology . 18 . 2 . 859–71 . Feb 1998 . 9447982 . 108797 . 10.1128/mcb.18.2.859.
• Melville MW, Tan SL, Wambach M, Song J, Morimoto RI, Katze MG . 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 . Feb 1999 . 9920933 . 10.1074/jbc.274.6.3797 . free .
• Ohtsuka K, Hata M . Mammalian HSP40/DNAJ homologs: cloning of novel cDNAs and a proposal for their classification and nomenclature . Cell Stress & Chaperones . 5 . 2 . 98–112 . Apr 2000 . 10.1379/1466-1268(2000)005<0098:mhdhco>2.0.co;2 . 2024-03-28 . 11147971 . 312896 .
• Horng T, Barton GM, Medzhitov R . TIRAP: an adapter molecule in the Toll signaling pathway . Nature Immunology . 2 . 9 . 835–41 . Sep 2001 . 11526399 . 10.1038/ni0901-835 . 7296195 .
• Yan W, Gale MJ, Tan SL, Katze MG . 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 . Apr 2002 . 11939789 . 10.1021/bi0121499 .
• Ladiges W, Morton J, Hopkins H, Wilson R, Filley G, Ware C, Gale M . Expression of human PKR protein kinase in transgenic mice . Journal of Interferon & Cytokine Research . 22 . 3 . 329–34 . Mar 2002 . 12034040 . 10.1089/107999002753675758 .
• Yan W, Frank CL, Korth MJ, Sopher BL, Novoa I, Ron D, Katze MG . Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK . Proceedings of the National Academy of Sciences of the United States of America . 99 . 25 . 15920–5 . Dec 2002 . 12446838 . 138540 . 10.1073/pnas.252341799 . 2002PNAS...9915920Y . free .
• van Huizen R, Martindale JL, Gorospe M, Holbrook NJ . P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling . The Journal of Biological Chemistry . 278 . 18 . 15558–64 . May 2003 . 12601012 . 10.1074/jbc.M212074200 . free .

Notes and References

1. Lee TG, Tang N, Thompson S, Miller J, Katze MG . The 58,000-dalton cellular inhibitor of the interferon-induced double-stranded RNA-activated protein kinase (PKR) is a member of the tetratricopeptide repeat family of proteins . Molecular and Cellular Biology . 14 . 4 . 2331–42 . Apr 1994 . 7511204 . 358600 . 10.1128/mcb.14.4.2331 .
2. Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E, Tsui LC . Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q . Genomics . 31 . 2 . 230–3 . Jan 1996 . 8824806 . 10.1006/geno.1996.0036 . free .
3. Web site: Entrez Gene: DNAJC3 DnaJ (Hsp40) homolog, subfamily C, member 3.
4. Synofzik M, Haack TB, Kopajtich R, Gorza M, Rapaport D, Greiner M, Schönfeld C, Freiberg C, Schorr S, Holl RW, Gonzalez MA, Fritsche A, Fallier-Becker P, Zimmermann R, Strom TM, Meitinger T, Züchner S, Schüle R, Schöls L, Prokisch H . Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration . American Journal of Human Genetics . 95 . 6 . 689–97 . Dec 2014 . 25466870 . 10.1016/j.ajhg.2014.10.013 . 4259973.
5. Lin Y, Sun Z . In vivo pancreatic β-cell-specific expression of antiaging gene Klotho: a novel approach for preserving β-cells in type 2 diabetes . Diabetes . 64 . 4 . 1444–58 . Apr 2015 . 25377875 . 10.2337/db14-0632 . 4375073.
6. Polyak SJ, Tang N, Wambach M, Barber GN, Katze MG . 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 . Jan 1996 . 8576172 . 10.1074/jbc.271.3.1702 . free .
7. Gale M, Blakely CM, Hopkins DA, Melville MW, Wambach M, Romano PR, Katze MG . Regulation of interferon-induced protein kinase PKR: modulation of P58IPK inhibitory function by a novel protein, P52rIPK . Molecular and Cellular Biology . 18 . 2 . 859–71 . Feb 1998 . 9447982 . 108797 . 10.1128/mcb.18.2.859.
8. Yan W, Frank CL, Korth MJ, Sopher BL, Novoa I, Ron D, Katze MG . Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK . Proceedings of the National Academy of Sciences of the United States of America . 99 . 25 . 15920–5 . Dec 2002 . 12446838 . 138540 . 10.1073/pnas.252341799 . 2002PNAS...9915920Y . free .