DNAJA3 explained

DnaJ homolog subfamily A member 3, mitochondrial, also known as Tumorous imaginal disc 1 (TID1), is a protein that in humans is encoded by the DNAJA3 gene on chromosome 16.^{[1] [2]} This protein belongs to the DNAJ/Hsp40 protein family, which is known for binding and activating Hsp70 chaperone proteins to perform protein folding, degradation, and complex assembly.^{[2] [3] [4]} As a mitochondrial protein, it is involved in maintaining membrane potential and mitochondrial DNA (mtDNA) integrity, as well as cellular processes such as cell movement, growth, and death.^{[2] [3] [5] [6] [7]} Furthermore, it is associated with a broad range of diseases, including neurodegenerative diseases, inflammatory diseases, and cancers.^{[3] [5] [7] [8]}

Structure

As a member of the DNAJ/Hsp40 protein family, DNAJA3 contains a conserved DnaJ domain, which includes an HPD motif that interacts with Hsp70 to perform its cochaperone function.^{[2] [3] [4] [5] [6]} The DnaJ domain is composed of tetrahelical regions containing a tripeptide of histidine, proline and aspartic acid situated between two helices. In addition, this protein contains a glycine/phenylalanine (G/F) rich linker region and a central cysteine-rich region similar to a zinc finger repeat, both characteristic of type I DnaJ molecular chaperones.^{[4] [5] [6]} The mitochondrial targeting sequence at its N-terminal directs the localization of the protein to the mitochondrial matrix.^{[4] [5] [6]}

DNAJA3 possesses two alternatively spliced forms: a long isoform of 43 kDa and a short isoform of 40 kDa.^{[2] [3] [5] [8]} The long isoform contains an additional 33 residues at its C-terminal compared to the short isoform, and this region is predicted to hinder the long isoform from regulating membrane potential.^[3]

Function

DNAJA3 is a member of the DNAJ/Hsp40 protein family, which stimulates the ATPase activity of Hsp70 chaperones and plays critical roles in protein folding, degradation, and multiprotein complex assembly.^{[2] [3] [4]} DNAJA3 localizes to the mitochondria, where it interacts with the mitochondrial Hsp70 chaperone (mtHsp70) to carry out the chaperone system.^{[2] [3]} This protein is crucial for maintaining a homogeneous distribution of mitochondrial membrane potential and the integrity of mtDNA. DNAJA3 homogenizes membrane potential through regulation of complex I aggregation, though the mechanism for maintaining mtDNA remains unknown.^[3] These functions then allow DNAJA3 to mediate mitochondrial fission through DRP1 and, by extension, cellular processes such as cell movement, growth, proliferation, differentiation, senescence, and apoptosis.^{[2] [3] [5] [6] [7]} However, though both isoforms of DNAJA3 are involved with cell survival, they are also observed to influence two opposing outcomes. The proapoptotic long isoform induces apoptosis by stimulating cytochrome C release and caspase activation in the mitochondria, whereas the antiapoptotic short isoform prevents cytochrome C release and, thus, apoptosis.^{[3] [7]} In neuromuscular junctions, only the short isoform clusters acetylcholine receptors for efficient synaptic transmission.^[3] The two isoforms also differ in their specific mitochondrial localization, which may partially account for their different functions.^{[3] [7]}

Before localization to the mitochondria, DNAJA3 is transiently retained in the cytosol, where it can also interact with cytosolic proteins and possibly function to transport these proteins.^{[4] [7]}

Clinical significance

This protein is implicated in several cancers, including skin cancer, breast cancer, and colorectal cancer.^[8] It is a key player in tumor suppression through interactions with oncogenic proteins, including ErbB2 and the p53 tumor suppressor protein.^{[2] [4]} Under hypoxic conditions, DNAJA3 may directly influence p53 complex assembly or modification, or indirectly ubiquitinylate p53 through ubiquitin ligases like MDM2. Moreover, both p53 and DNAJA3 must be present in the mitochondria in order to induce apoptosis in the cell.^[4] In head and neck squamous cell carcinoma (HNSCC) cancer, DNAJA3 suppresses cell proliferation, anchorage-independent growth, cell motility, and cell invasion by attenuating EGFR and, downstream the signaling pathway, AKT.^[8] Thus, treatments promoting DNAJA3 expression and function may greatly aid the elimination of tumors.^[4]

Additionally, DNAJA3 is implicated in neurodegenerative diseases like Parkinson's disease by virtue of its key roles in chaperoning mitochondrial proteins and mediating mitochondrial morphology in conjunction with mtHsp70.^{[3] [5]} Another disease, psoriasis, is a chronic inflammatory skin disease that results from the absence of DNAJA3 activity, which then results in the activation of MK5, increased phosphorylation of HSP27, increased actin cytoskeleton organization, and hyperthickened skin.^[7]

Interactions

DNAJA3 has been shown to interact with:

• ErbB-2 receptor tyrosine kinase^[6]
• MK5^[7]
• HSPA9^[3]
• HSPA8,^[9]
• JAK2,^[9] and
• RASA1^[10]

Further reading

• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 . etal.
• Syken J, De-Medina T, Münger K . TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two mitochondrial modulators of apoptosis with opposing functions . Proc. Natl. Acad. Sci. U.S.A. . 96 . 15 . 8499–504 . 1999 . 10411904 . 10.1073/pnas.96.15.8499 . 17545 . 1999PNAS...96.8499S . free .
• Shinohara M, Gasior SL, Bishop DK, Shinohara A. Tid1/Rdh54 promotes colocalization of rad51 and dmc1 during meiotic recombination . Proc. Natl. Acad. Sci. U.S.A. . 97 . 20 . 10814–9 . 2000 . 11005857 . 10.1073/pnas.97.20.10814 . 27106 . 2000PNAS...9710814S . free .
• Trentin GA, Yin X, Tahir S . A mouse homologue of the Drosophila tumor suppressor l(2)tid gene defines a novel Ras GTPase-activating protein (RasGAP)-binding protein . J. Biol. Chem. . 276 . 16 . 13087–95 . 2001 . 11116152 . 10.1074/jbc.M009267200 . etal. 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 . 2001 . 10.1379/1466-1268(2000)005<0098:mhdhco>2.0.co;2 . 2024-02-01 . 11147971 . 312896 . 1466-1268 .
• Sarkar S, Pollack BP, Lin KT . hTid-1, a human DnaJ protein, modulates the interferon signaling pathway . J. Biol. Chem. . 276 . 52 . 49034–42 . 2002 . 11679576 . 10.1074/jbc.M103683200 . etal. free .
• Yin X, Rozakis-Adcock M . Genomic organization and expression of the human tumorous imaginal disc (TID1) gene . Gene . 278 . 1–2 . 201–10 . 2002 . 11707338 . 10.1016/S0378-1119(01)00720-X .
• Cheng H, Cenciarelli C, Shao Z . Human T cell leukemia virus type 1 Tax associates with a molecular chaperone complex containing hTid-1 and Hsp70 . Curr. Biol. . 11 . 22 . 1771–5 . 2002 . 11719219 . 10.1016/S0960-9822(01)00540-1 . 17461974 . etal. free .
• Cheng H, Cenciarelli C, Tao M . HTLV-1 Tax-associated hTid-1, a human DnaJ protein, is a repressor of Ikappa B kinase beta subunit . J. Biol. Chem. . 277 . 23 . 20605–10 . 2002 . 11927590 . 10.1074/jbc.M201204200 . etal. free .
• Wang Y, Han KJ, Pang XW . Large scale identification of human hepatocellular carcinoma-associated antigens by autoantibodies . J. Immunol. . 169 . 2 . 1102–9 . 2002 . 12097419 . 10.4049/jimmunol.169.2.1102. etal. free .
• Sasaki S, Nakamura T, Arakawa H . Isolation and characterization of a novel gene, hRFI, preferentially expressed in esophageal cancer . Oncogene . 21 . 32 . 5024–30 . 2002 . 12118383 . 10.1038/sj.onc.1205627 . etal. free .
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . etal . 2002PNAS...9916899M. free .
• Syken J, Macian F, Agarwal S . TID1, a mammalian homologue of the drosophila tumor suppressor lethal(2) tumorous imaginal discs, regulates activation-induced cell death in Th2 cells . Oncogene . 22 . 30 . 4636–41 . 2003 . 12879007 . 10.1038/sj.onc.1206569 . etal. free .
• Rodriguez M, Yu X, Chen J, Songyang Z . Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains . J. Biol. Chem. . 278 . 52 . 52914–8 . 2004 . 14578343 . 10.1074/jbc.C300407200 . free .
• Ota T, Suzuki Y, Nishikawa T . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . etal. free .
• Lo JF, Hayashi M, Woo-Kim S . Tid1, a cochaperone of the heat shock 70 protein and the mammalian counterpart of the Drosophila tumor suppressor l(2)tid, is critical for early embryonic development and cell survival . Mol. Cell. Biol. . 24 . 6 . 2226–36 . 2004 . 14993262 . 10.1128/MCB.24.6.2226-2236.2004 . 355836 . etal.
• Edwards KM, Münger K . Depletion of physiological levels of the human TID1 protein renders cancer cell lines resistant to apoptosis mediated by multiple exogenous stimuli . Oncogene . 23 . 52 . 8419–31 . 2004 . 15156195 . 10.1038/sj.onc.1207732 . free .
• Colland F, Jacq X, Trouplin V . Functional proteomics mapping of a human signaling pathway . Genome Res. . 14 . 7 . 1324–32 . 2004 . 15231748 . 10.1101/gr.2334104 . 442148 . etal.

Notes and References

1. Schilling B, De-Medina T, Syken J, Vidal M, Munger K . A novel human DnaJ protein, hTid-1, a homolog of the Drosophila tumor suppressor protein Tid56, can interact with the human papillomavirus type 16 E7 oncoprotein . Virology . 247 . 1 . 74–85 . August 1998. 9683573 . 10.1006/viro.1998.9220 . free .
2. Web site: Entrez Gene: DNAJA3 DnaJ (Hsp40) homolog, subfamily A, member 3.
3. Ng. AC. Baird. SD. Screaton. RA. Essential role of TID1 in maintaining mitochondrial membrane potential homogeneity and mitochondrial DNA integrity.. Molecular and Cellular Biology. April 2014. 34. 8. 1427–37. 24492964. 10.1128/mcb.01021-13. 3993590.
4. Ahn. BY. Trinh. DL. Zajchowski. LD. Lee. B. Elwi. AN. Kim. SW. Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer.. Oncogene. 25 February 2010. 29. 8. 1155–66. 19935715. 10.1038/onc.2009.413. free.
5. Elwi. AN. Lee. B. Meijndert. HC. Braun. JE. Kim. SW. Mitochondrial chaperone DnaJA3 induces Drp1-dependent mitochondrial fragmentation.. The International Journal of Biochemistry & Cell Biology. August 2012. 44. 8. 1366–76. 22595283. 10.1016/j.biocel.2012.05.004.
6. Trinh. DL. Elwi. AN. Kim. SW. Direct interaction between p53 and Tid1 proteins affects p53 mitochondrial localization and apoptosis.. Oncotarget. October 2010. 1. 6. 396–404. 21311096. 10.18632/oncotarget.100902. 3248115. 31 January 2024.
7. Choi. JH. Choi. DK. Sohn. KC. Kwak. SS. Suk. J. Lim. JS. Shin. I. Kim. SW. Lee. JH. Joe. CO. Absence of a human DnaJ protein hTid-1S correlates with aberrant actin cytoskeleton organization in lesional psoriatic skin.. The Journal of Biological Chemistry. 27 July 2012. 287. 31. 25954–63. 22692211. 10.1074/jbc.m111.313809. 3406679. free.
8. Chen. CY. Chiou. SH. Huang. CY. Jan. CI. Lin. SC. Hu. WY. Chou. SH. Liu. CJ. Lo. JF. Tid1 functions as a tumour suppressor in head and neck squamous cell carcinoma.. The Journal of Pathology. November 2009. 219. 3. 347–55. 19681071. 10.1002/path.2604. 23405415.
9. December 2001 . Sarkar S, Pollack BP, Lin KT, Kotenko SV, Cook JR, Lewis A, Pestka S . hTid-1, a human DnaJ protein, modulates the interferon signaling pathway . J. Biol. Chem. . 276 . 52 . 49034–42 . 11679576 . 10.1074/jbc.M103683200. free .
10. April 2001 . Trentin GA, Yin X, Tahir S, Lhotak S, Farhang-Fallah J, Li Y, Rozakis-Adcock M . A mouse homologue of the Drosophila tumor suppressor l(2)tid gene defines a novel Ras GTPase-activating protein (RasGAP)-binding protein . J. Biol. Chem. . 276 . 16 . 13087–95 . 11116152 . 10.1074/jbc.M009267200. free .