DNAJC3
DnaJ homolog subfamily C member 3 is a protein that in humans is encoded by the DNAJC3 gene.[5][6][7]
Function
[edit]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).[7]
Clinical significance
[edit]An important role for DNAJC3 has been attributed to diabetes mellitus as well as multi system neurodegeneration.[8][9] 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.[8] Notably, the DNAJC3 protein is also considered as an important marker for stress in the endoplasmatic reticulum. [9]
Interactions
[edit]DNAJC3 has been shown to interact with:
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000102580 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022136 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Lee TG, Tang N, Thompson S, Miller J, Katze MG (Apr 1994). "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. doi:10.1128/mcb.14.4.2331. PMC 358600. PMID 7511204.
- ^ Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E, Tsui LC (Jan 1996). "Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q". Genomics. 31 (2): 230–3. doi:10.1006/geno.1996.0036. PMID 8824806.
- ^ a b "Entrez Gene: DNAJC3 DnaJ (Hsp40) homolog, subfamily C, member 3".
- ^ a b 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 (Dec 2014). "Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration". American Journal of Human Genetics. 95 (6): 689–97. doi:10.1016/j.ajhg.2014.10.013. PMC 4259973. PMID 25466870.
- ^ a b Lin Y, Sun Z (Apr 2015). "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. doi:10.2337/db14-0632. PMC 4375073. PMID 25377875.
- ^ 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. PMID 8576172.
- ^ a b Gale M, Blakely CM, Hopkins DA, Melville MW, Wambach M, Romano PR, Katze MG (Feb 1998). "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. doi:10.1128/mcb.18.2.859. PMC 108797. PMID 9447982.
- ^ Yan W, Frank CL, Korth MJ, Sopher BL, Novoa I, Ron D, Katze MG (Dec 2002). "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. Bibcode:2002PNAS...9915920Y. doi:10.1073/pnas.252341799. PMC 138540. PMID 12446838.
Further reading
[edit]- 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. PMID 8576172.
- 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. PMID 8666242.
- 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. PMID 8824808.
- Gale M, Blakely CM, Hopkins DA, Melville MW, Wambach M, Romano PR, Katze MG (Feb 1998). "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. doi:10.1128/mcb.18.2.859. PMC 108797. PMID 9447982.
- 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. PMID 9920933.
- Ohtsuka K, Hata M (Apr 2000). "Mammalian HSP40/DNAJ homologs: cloning of novel cDNAs and a proposal for their classification and nomenclature". Cell Stress & Chaperones. 5 (2): 98–112. doi:10.1379/1466-1268(2000)005<0098:mhdhco>2.0.co;2 (inactive 2024-11-02). PMC 312896. PMID 11147971.
{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link) - 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. PMID 11526399. S2CID 7296195.
- 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. PMID 11939789.
- 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. PMID 12034040.
- Yan W, Frank CL, Korth MJ, Sopher BL, Novoa I, Ron D, Katze MG (Dec 2002). "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. Bibcode:2002PNAS...9915920Y. doi:10.1073/pnas.252341799. PMC 138540. PMID 12446838.
- 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. PMID 12601012.