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{{Infobox_gene}}
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
'''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.<ref name="pmid9683573">{{cite journal |vauthors=Schilling B, De-Medina T, Syken J, Vidal M, Munger K | title = 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 | journal = Virology | volume = 247 | issue = 1 | pages = 74–85 | date=August 1998| pmid = 9683573 | pmc = | doi = 10.1006/viro.1998.9220 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: DNAJA3 DnaJ (Hsp40) homolog, subfamily A, member 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9093| accessdate = }}</ref><ref name="pmid24492964"/> This protein belongs to the DNAJ/[[Hsp40]] protein family, which is known for binding and activating [[Hsp70]] [[chaperone (protein)|chaperone]] proteins to perform protein folding, degradation, and complex assembly.<ref name="entrez"/><ref name="pmid24492964">{{cite journal|last1=Ng|first1=AC|last2=Baird|first2=SD|last3=Screaton|first3=RA|title=Essential role of TID1 in maintaining mitochondrial membrane potential homogeneity and mitochondrial DNA integrity.|journal=Molecular and Cellular Biology|date=April 2014|volume=34|issue=8|pages=1427–37|pmid=24492964|doi=10.1128/mcb.01021-13|pmc=3993590}}</ref><ref name="pmid19935715">{{cite journal|last1=Ahn|first1=BY|last2=Trinh|first2=DL|last3=Zajchowski|first3=LD|last4=Lee|first4=B|last5=Elwi|first5=AN|last6=Kim|first6=SW|title=Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer.|journal=Oncogene|date=25 February 2010|volume=29|issue=8|pages=1155–66|pmid=19935715|doi=10.1038/onc.2009.413}}</ref> 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 [[apoptosis|death]].<ref name="entrez"/><ref name="pmid24492964"/><ref name="pmid22595283">{{cite journal|last1=Elwi|first1=AN|last2=Lee|first2=B|last3=Meijndert|first3=HC|last4=Braun|first4=JE|last5=Kim|first5=SW|title=Mitochondrial chaperone DnaJA3 induces Drp1-dependent mitochondrial fragmentation.|journal=The International Journal of Biochemistry & Cell Biology|date=August 2012|volume=44|issue=8|pages=1366–76|pmid=22595283|doi=10.1016/j.biocel.2012.05.004}}</ref><ref name="pmid21311096">{{cite journal|last1=Trinh|first1=DL|last2=Elwi|first2=AN|last3=Kim|first3=SW|title=Direct interaction between p53 and Tid1 proteins affects p53 mitochondrial localization and apoptosis.|journal=Oncotarget|date=October 2010|volume=1|issue=6|pages=396–404|pmid=21311096|doi=10.18632/oncotarget.100902|pmc=3248115}}</ref><ref name="pmid22692211">{{cite journal|last1=Choi|first1=JH|last2=Choi|first2=DK|last3=Sohn|first3=KC|last4=Kwak|first4=SS|last5=Suk|first5=J|last6=Lim|first6=JS|last7=Shin|first7=I|last8=Kim|first8=SW|last9=Lee|first9=JH|last10=Joe|first10=CO|title=Absence of a human DnaJ protein hTid-1S correlates with aberrant actin cytoskeleton organization in lesional psoriatic skin.|journal=The Journal of Biological Chemistry|date=27 July 2012|volume=287|issue=31|pages=25954–63|pmid=22692211|doi=10.1074/jbc.m111.313809|pmc=3406679}}</ref> Furthermore, it is associated with a broad range of [[disease]]s, including [[neurodegenerative diseases]], [[inflammatory diseases]], and [[cancer]]s.<ref name="pmid24492964"/><ref name="pmid22595283"/><ref name="pmid22692211"/><ref name="pmid19681071">{{cite journal|last1=Chen|first1=CY|last2=Chiou|first2=SH|last3=Huang|first3=CY|last4=Jan|first4=CI|last5=Lin|first5=SC|last6=Hu|first6=WY|last7=Chou|first7=SH|last8=Liu|first8=CJ|last9=Lo|first9=JF|title=Tid1 functions as a tumour suppressor in head and neck squamous cell carcinoma.|journal=The Journal of pathology|date=November 2009|volume=219|issue=3|pages=347–55|pmid=19681071|doi=10.1002/path.2604}}</ref>
{{GNF_Protein_box
| image = PBB_Protein_DNAJA3_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2ctt.
  | PDB = {{PDB2|2ctt}}, {{PDB2|2dn9}}
| Name = DnaJ (Hsp40) homolog, subfamily A, member 3
| HGNCid = 11808
| Symbol = DNAJA3
| AltSymbols =; FLJ45758; TID1; hTid-1
| OMIM = 608382
| ECnumber =
| Homologene = 36170
| MGIid = 1933786
| GeneAtlas_image1 = PBB_GE_DNAJA3_205963_s_at_tn.png
| Function = {{GNF_GO|id=GO:0005083 |text = small GTPase regulator activity}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0031072 |text = heat shock protein binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}} {{GNF_GO|id=GO:0051082 |text = unfolded protein binding}}  
  | Component = {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005739 |text = mitochondrion}} {{GNF_GO|id=GO:0005759 |text = mitochondrial matrix}} {{GNF_GO|id=GO:0005829 |text = cytosol}}
| Process = {{GNF_GO|id=GO:0006457 |text = protein folding}} {{GNF_GO|id=GO:0007264 |text = small GTPase mediated signal transduction}} {{GNF_GO|id=GO:0042981 |text = regulation of apoptosis}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 9093
    | Hs_Ensembl = ENSG00000103423
    | Hs_RefseqProtein = NP_005138
    | Hs_RefseqmRNA = NM_005147
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 16
    | Hs_GenLoc_start = 4415854
    | Hs_GenLoc_end = 4446774
    | Hs_Uniprot = Q96EY1
    | Mm_EntrezGene = 83945
    | Mm_Ensembl = ENSMUSG00000004069
    | Mm_RefseqmRNA = NM_023646
    | Mm_RefseqProtein = NP_076135
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 16
    | Mm_GenLoc_start = 4599351
    | Mm_GenLoc_end = 4622919
    | Mm_Uniprot = Q3TJA9
  }}
}}
'''DnaJ (Hsp40) homolog, subfamily A, member 3''', also known as '''DNAJA3''', is a human [[gene]].


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{PBB_Summary
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.<ref name="entrez"/><ref name="pmid24492964"/><ref name="pmid19935715"/><ref name="pmid22595283"/><ref name="pmid21311096"/> 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.<ref name="pmid19935715"/><ref name="pmid22595283"/><ref name="pmid21311096"/> The [[mitochondria]]l targeting sequence at its N-terminal directs the localization of the protein to the [[mitochondrial matrix]].<ref name="pmid19935715"/><ref name="pmid22595283"/><ref name="pmid21311096"/>
| section_title =  
| summary_text = DNAJA3 belongs to the evolutionarily conserved DNAJ/HSP40 family of proteins. For background information on the DNAJ family, see MIM 608375.[supplied by OMIM]<ref name="entrez">{{cite web | title = Entrez Gene: DNAJA3 DnaJ (Hsp40) homolog, subfamily A, member 3| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9093| accessdate = }}</ref>
}}


==References==
DNAJA3 possesses two [[alternative splicing|alternatively spliced]] forms: a long [[isoform]] of 43 kDa and a short isoform of 40 kDa.<ref name="entrez"/><ref name="pmid24492964"/><ref name="pmid22595283"/><ref name="pmid19681071"/> 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.<ref name="pmid24492964"/>
{{reflist|2}}


==Further reading==
== 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]], [[protein degradation|degradation]], and [[multiprotein complex]] assembly.<ref name="entrez"/><ref name="pmid24492964"/><ref name="pmid19935715"/> DNAJA3 [[subcellular localization|localizes]] to the mitochondria, where it interacts with the mitochondrial Hsp70 chaperone ([[HSPA9|mtHsp70]]) to carry out the chaperone system.<ref name="entrez"/><ref name="pmid24492964"/> 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.<ref name="pmid24492964"/> These functions then allow DNAJA3 to mediate [[mitochondrial fission]] through [[DNM1L|DRP1]] and, by extension, cellular processes such as cell [[cell migration|movement]], [[cell growth|growth]], proliferation, [[Cellular differentiation|differentiation]], [[senescence]], and [[apoptosis]].<ref name="entrez"/><ref name="pmid24492964"/><ref name="pmid22595283"/><ref name="pmid21311096"/><ref name="pmid22692211"/> 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.<ref name="pmid24492964"/><ref name="pmid22692211"/> In [[neuromuscular junction]]s, only the short isoform clusters [[acetylcholine receptor]]s for efficient [[synaptic transmission]].<ref name="pmid24492964"/> The two isoforms also differ in their specific mitochondrial localization, which may partially account for their different functions.<ref name="pmid24492964"/><ref name="pmid22692211"/>
 
Before localization to the mitochondria, DNAJA3 is transiently retained in the cytosol, where it can also interact with [[cytosol]]ic proteins and possibly function to [[protein translocation|transport]] these proteins.<ref name="pmid19935715"/><ref name="pmid22692211"/>
 
== Clinical significance ==
 
This protein is implicated in several cancers, including [[skin cancer]], [[breast cancer]], and [[colorectal cancer]].<ref name="pmid19681071"/> It is a key player in tumor suppression through interactions with [[oncogenic]] proteins, including [[ErbB2]] and the [[p53]] tumor suppressor protein.<ref name="entrez"/><ref name="pmid19935715"/> Under hypoxic conditions, DNAJA3 may directly influence p53 complex assembly or modification, or indirectly ubiquitinylate p53 through [[ubiquitin ligase]]s like [[MDM2]]. Moreover, both p53 and DNAJA3 must be present in the mitochondria in order to induce apoptosis in the cell.<ref name="pmid19935715"/> In head and neck squamous cell carcinoma ([[HNSCC]]) cancer, DNAJA3 suppresses cell proliferation, anchorage-independent growth, cell motility, and cell invasion by attenuating [[Epidermal growth factor receptor|EGFR]] and, downstream the signaling pathway, [[AKT]].<ref name="pmid19681071"/> Thus, treatments promoting DNAJA3 expression and function may greatly aid the elimination of tumors.<ref name="pmid19935715"/>
 
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.<ref name="pmid24492964"/><ref name="pmid22595283"/> Another disease, [[psoriasis]], is a [[chronic condition|chronic]] [[inflammation|inflammatory]] skin disease that results from the absence of DNAJA3 activity, which then results in the activation of [[MK5 (protein)|MK5]], increased [[phosphorylation]] of [[HSP27]], increased [[actin]] [[cytoskeleton]] organization, and hyperthickened skin.<ref name="pmid22692211"/>
 
== Interactions ==
 
DNAJA3 has been shown to [[Protein-protein interaction|interact]] with:
*[[ErbB-2 receptor]] tyrosine kinase<ref name="pmid21311096"/>
*[[MK5 (protein)|MK5]]<ref name="pmid22692211"/>
* [[HSPA9]]<ref name="pmid24492964"/>
* [[HSPA8]],<ref name = pmid11679576>{{cite journal | date = December 2001 |vauthors=Sarkar S, Pollack BP, Lin KT, Kotenko SV, Cook JR, Lewis A, Pestka S | title = hTid-1, a human DnaJ protein, modulates the interferon signaling pathway | journal = J. Biol. Chem. | volume = 276 | issue = 52 | pages = 49034–42 | pmid = 11679576 | doi = 10.1074/jbc.M103683200}}</ref>
* [[Janus kinase 2|JAK2]],<ref name = pmid11679576/> and
* [[RAS p21 protein activator 1|RASA1]]<ref name = pmid11116152>{{cite journal | date = April 2001 |vauthors=Trentin GA, Yin X, Tahir S, Lhotak S, Farhang-Fallah J, Li Y, Rozakis-Adcock M | title = A mouse homologue of the Drosophila tumor suppressor l(2)tid gene defines a novel Ras GTPase-activating protein (RasGAP)-binding protein | journal = J. Biol. Chem. | volume = 276 | issue = 16 | pages = 13087–95 | pmid = 11116152 | doi = 10.1074/jbc.M009267200}}</ref>
 
== References ==
{{reflist}}
 
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
*{{cite journal  |vauthors=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1–2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=10.1016/0378-1119(94)90802-8 }}
| citations =
*{{cite journal  |vauthors=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library |journal=Gene |volume=200 |issue= 1–2 |pages= 149–56 |year= 1997 |pmid= 9373149 |doi=10.1016/S0378-1119(97)00411-3 |display-authors=etal}}
*{{cite journal  | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171-4 |year= 1994 |pmid= 8125298 |doi=  }}
*{{cite journal  |vauthors=Syken J, De-Medina T, Münger K |title=TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two mitochondrial modulators of apoptosis with opposing functions |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue= 15 |pages= 8499–504 |year= 1999 |pmid= 10411904 |doi=10.1073/pnas.96.15.8499  | pmc=17545  }}
*{{cite journal  | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149-56 |year= 1997 |pmid= 9373149 |doi=  }}
*{{cite journal  | author=Shinohara M, Gasior SL, Bishop DK, Shinohara A |title=Tid1/Rdh54 promotes colocalization of rad51 and dmc1 during meiotic recombination |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 20 |pages= 10814–9 |year= 2000 |pmid= 11005857 |doi=10.1073/pnas.97.20.10814  | pmc=27106  }}
*{{cite journal  | author=Schilling B, De-Medina T, Syken J, ''et al.'' |title=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. |journal=Virology |volume=247 |issue= 1 |pages= 74-85 |year= 1998 |pmid= 9683573 |doi= 10.1006/viro.1998.9220 }}
*{{cite journal  |vauthors=Trentin GA, Yin X, Tahir S |title=A mouse homologue of the Drosophila tumor suppressor l(2)tid gene defines a novel Ras GTPase-activating protein (RasGAP)-binding protein |journal=J. Biol. Chem. |volume=276 |issue= 16 |pages= 13087–95 |year= 2001 |pmid= 11116152 |doi= 10.1074/jbc.M009267200 |display-authors=etal}}
*{{cite journal  | author=Syken J, De-Medina T, Münger K |title=TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two mitochondrial modulators of apoptosis with opposing functions. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue= 15 |pages= 8499-504 |year= 1999 |pmid= 10411904 |doi= }}
*{{cite journal  |vauthors=Ohtsuka K, Hata M |title=Mammalian HSP40/DNAJ homologs: cloning of novel cDNAs and a proposal for their classification and nomenclature |journal=Cell Stress Chaperones |volume=5 |issue= 2 |pages= 98–112 |year= 2001 |pmid= 11147971 |doi=10.1379/1466-1268(2000)005<0098:MHDHCO>2.0.CO;2  | pmc=312896  | issn=1466-1268  }}
*{{cite journal  | author=Shinohara M, Gasior SL, Bishop DK, Shinohara A |title=Tid1/Rdh54 promotes colocalization of rad51 and dmc1 during meiotic recombination. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 20 |pages= 10814-9 |year= 2000 |pmid= 11005857 |doi= }}
*{{cite journal  |vauthors=Sarkar S, Pollack BP, Lin KT |title=hTid-1, a human DnaJ protein, modulates the interferon signaling pathway |journal=J. Biol. Chem. |volume=276 |issue= 52 |pages= 49034–42 |year= 2002 |pmid= 11679576 |doi= 10.1074/jbc.M103683200 |display-authors=etal}}
*{{cite journal  | author=Trentin GA, Yin X, Tahir S, ''et al.'' |title=A mouse homologue of the Drosophila tumor suppressor l(2)tid gene defines a novel Ras GTPase-activating protein (RasGAP)-binding protein. |journal=J. Biol. Chem. |volume=276 |issue= 16 |pages= 13087-95 |year= 2001 |pmid= 11116152 |doi= 10.1074/jbc.M009267200 }}
*{{cite journal  |vauthors=Yin X, Rozakis-Adcock M |title=Genomic organization and expression of the human tumorous imaginal disc (TID1) gene |journal=Gene |volume=278 |issue= 1–2 |pages= 201–10 |year= 2002 |pmid= 11707338 |doi=10.1016/S0378-1119(01)00720-X  }}
*{{cite journal  | author=Ohtsuka K, Hata M |title=Mammalian HSP40/DNAJ homologs: cloning of novel cDNAs and a proposal for their classification and nomenclature. |journal=Cell Stress Chaperones |volume=5 |issue= 2 |pages= 98-112 |year= 2001 |pmid= 11147971 |doi= }}
*{{cite journal  |vauthors=Cheng H, Cenciarelli C, Shao Z |title=Human T cell leukemia virus type 1 Tax associates with a molecular chaperone complex containing hTid-1 and Hsp70 |journal=Curr. Biol. |volume=11 |issue= 22 |pages= 1771–5 |year= 2002 |pmid= 11719219 |doi=10.1016/S0960-9822(01)00540-1 |display-authors=etal}}
*{{cite journal  | author=Sarkar S, Pollack BP, Lin KT, ''et al.'' |title=hTid-1, a human DnaJ protein, modulates the interferon signaling pathway. |journal=J. Biol. Chem. |volume=276 |issue= 52 |pages= 49034-42 |year= 2002 |pmid= 11679576 |doi= 10.1074/jbc.M103683200 }}
*{{cite journal  |vauthors=Cheng H, Cenciarelli C, Tao M |title=HTLV-1 Tax-associated hTid-1, a human DnaJ protein, is a repressor of Ikappa B kinase beta subunit |journal=J. Biol. Chem. |volume=277 |issue= 23 |pages= 20605–10 |year= 2002 |pmid= 11927590 |doi= 10.1074/jbc.M201204200 |display-authors=etal}}
*{{cite journal  | author=Yin X, Rozakis-Adcock M |title=Genomic organization and expression of the human tumorous imaginal disc (TID1) gene. |journal=Gene |volume=278 |issue= 1-2 |pages= 201-10 |year= 2002 |pmid= 11707338 |doi=  }}
*{{cite journal  |vauthors=Wang Y, Han KJ, Pang XW |title=Large scale identification of human hepatocellular carcinoma-associated antigens by autoantibodies |journal=J. Immunol. |volume=169 |issue= 2 |pages= 1102–9 |year= 2002 |pmid= 12097419 |doi= 10.4049/jimmunol.169.2.1102|display-authors=etal}}
*{{cite journal  | author=Cheng H, Cenciarelli C, Shao Z, ''et al.'' |title=Human T cell leukemia virus type 1 Tax associates with a molecular chaperone complex containing hTid-1 and Hsp70. |journal=Curr. Biol. |volume=11 |issue= 22 |pages= 1771-5 |year= 2002 |pmid= 11719219 |doi= }}
*{{cite journal  |vauthors=Sasaki S, Nakamura T, Arakawa H |title=Isolation and characterization of a novel gene, hRFI, preferentially expressed in esophageal cancer |journal=Oncogene |volume=21 |issue= 32 |pages= 5024–30 |year= 2002 |pmid= 12118383 |doi= 10.1038/sj.onc.1205627 |display-authors=etal}}
*{{cite journal  | author=Cheng H, Cenciarelli C, Tao M, ''et al.'' |title=HTLV-1 Tax-associated hTid-1, a human DnaJ protein, is a repressor of Ikappa B kinase beta subunit. |journal=J. Biol. Chem. |volume=277 |issue= 23 |pages= 20605-10 |year= 2002 |pmid= 11927590 |doi= 10.1074/jbc.M201204200 }}
*{{cite journal  |vauthors=Strausberg RL, Feingold EA, Grouse LH |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241 |display-authors=etal}}
*{{cite journal  | author=Wang Y, Han KJ, Pang XW, ''et al.'' |title=Large scale identification of human hepatocellular carcinoma-associated antigens by autoantibodies. |journal=J. Immunol. |volume=169 |issue= 2 |pages= 1102-9 |year= 2002 |pmid= 12097419 |doi= }}
*{{cite journal  |vauthors=Syken J, Macian F, Agarwal S |title=TID1, a mammalian homologue of the drosophila tumor suppressor lethal(2) tumorous imaginal discs, regulates activation-induced cell death in Th2 cells |journal=Oncogene |volume=22 |issue= 30 |pages= 4636–41 |year= 2003 |pmid= 12879007 |doi= 10.1038/sj.onc.1206569 |display-authors=etal}}
*{{cite journal  | author=Sasaki S, Nakamura T, Arakawa H, ''et al.'' |title=Isolation and characterization of a novel gene, hRFI, preferentially expressed in esophageal cancer. |journal=Oncogene |volume=21 |issue= 32 |pages= 5024-30 |year= 2002 |pmid= 12118383 |doi= 10.1038/sj.onc.1205627 }}
*{{cite journal  |vauthors=Rodriguez M, Yu X, Chen J, Songyang Z |title=Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains |journal=J. Biol. Chem. |volume=278 |issue= 52 |pages= 52914–8 |year= 2004 |pmid= 14578343 |doi= 10.1074/jbc.C300407200 }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal  |vauthors=Ota T, Suzuki Y, Nishikawa T |title=Complete sequencing and characterization of 21,243 full-length human cDNAs |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 |display-authors=etal}}
*{{cite journal  | author=Syken J, Macian F, Agarwal S, ''et al.'' |title=TID1, a mammalian homologue of the drosophila tumor suppressor lethal(2) tumorous imaginal discs, regulates activation-induced cell death in Th2 cells. |journal=Oncogene |volume=22 |issue= 30 |pages= 4636-41 |year= 2003 |pmid= 12879007 |doi= 10.1038/sj.onc.1206569 }}
*{{cite journal  |vauthors=Lo JF, Hayashi M, Woo-Kim S |title=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 |journal=Mol. Cell. Biol. |volume=24 |issue= 6 |pages= 2226–36 |year= 2004 |pmid= 14993262 |doi=10.1128/MCB.24.6.2226-2236.2004  | pmc=355836  |display-authors=etal}}
*{{cite journal  | author=Rodriguez M, Yu X, Chen J, Songyang Z |title=Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains. |journal=J. Biol. Chem. |volume=278 |issue= 52 |pages= 52914-8 |year= 2004 |pmid= 14578343 |doi= 10.1074/jbc.C300407200 }}
*{{cite journal  |vauthors=Edwards KM, Münger K |title=Depletion of physiological levels of the human TID1 protein renders cancer cell lines resistant to apoptosis mediated by multiple exogenous stimuli |journal=Oncogene |volume=23 |issue= 52 |pages= 8419–31 |year= 2004 |pmid= 15156195 |doi= 10.1038/sj.onc.1207732 }}
*{{cite journal  | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
*{{cite journal  |vauthors=Colland F, Jacq X, Trouplin V |title=Functional proteomics mapping of a human signaling pathway |journal=Genome Res. |volume=14 |issue= 7 |pages= 1324–32 |year= 2004 |pmid= 15231748 |doi= 10.1101/gr.2334104 | pmc=442148 |display-authors=etal}}
*{{cite journal  | author=Lo JF, Hayashi M, Woo-Kim S, ''et al.'' |title=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. |journal=Mol. Cell. Biol. |volume=24 |issue= 6 |pages= 2226-36 |year= 2004 |pmid= 14993262 |doi= }}
*{{cite journal  | author=Edwards KM, Münger K |title=Depletion of physiological levels of the human TID1 protein renders cancer cell lines resistant to apoptosis mediated by multiple exogenous stimuli. |journal=Oncogene |volume=23 |issue= 52 |pages= 8419-31 |year= 2004 |pmid= 15156195 |doi= 10.1038/sj.onc.1207732 }}
*{{cite journal | author=Colland F, Jacq X, Trouplin V, ''et al.'' |title=Functional proteomics mapping of a human signaling pathway. |journal=Genome Res. |volume=14 |issue= 7 |pages= 1324-32 |year= 2004 |pmid= 15231748 |doi= 10.1101/gr.2334104 }}
}}
{{refend}}
{{refend}}


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[[Category:Heat shock proteins]]

Revision as of 03:26, 15 November 2017

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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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][3] 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:

References

  1. ↑ Schilling B, De-Medina T, Syken J, Vidal M, Munger K (August 1998). "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. doi:10.1006/viro.1998.9220. PMID 9683573.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "Entrez Gene: DNAJA3 DnaJ (Hsp40) homolog, subfamily A, member 3".
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 Ng, AC; Baird, SD; Screaton, RA (April 2014). "Essential role of TID1 in maintaining mitochondrial membrane potential homogeneity and mitochondrial DNA integrity". Molecular and Cellular Biology. 34 (8): 1427–37. doi:10.1128/mcb.01021-13. PMC 3993590. PMID 24492964.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Ahn, BY; Trinh, DL; Zajchowski, LD; Lee, B; Elwi, AN; Kim, SW (25 February 2010). "Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer". Oncogene. 29 (8): 1155–66. doi:10.1038/onc.2009.413. PMID 19935715.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 Elwi, AN; Lee, B; Meijndert, HC; Braun, JE; Kim, SW (August 2012). "Mitochondrial chaperone DnaJA3 induces Drp1-dependent mitochondrial fragmentation". The International Journal of Biochemistry & Cell Biology. 44 (8): 1366–76. doi:10.1016/j.biocel.2012.05.004. PMID 22595283.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Trinh, DL; Elwi, AN; Kim, SW (October 2010). "Direct interaction between p53 and Tid1 proteins affects p53 mitochondrial localization and apoptosis". Oncotarget. 1 (6): 396–404. doi:10.18632/oncotarget.100902. PMC 3248115. PMID 21311096.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Choi, JH; Choi, DK; Sohn, KC; Kwak, SS; Suk, J; Lim, JS; Shin, I; Kim, SW; Lee, JH; Joe, CO (27 July 2012). "Absence of a human DnaJ protein hTid-1S correlates with aberrant actin cytoskeleton organization in lesional psoriatic skin". The Journal of Biological Chemistry. 287 (31): 25954–63. doi:10.1074/jbc.m111.313809. PMC 3406679. PMID 22692211.
  8. ↑ 8.0 8.1 8.2 8.3 Chen, CY; Chiou, SH; Huang, CY; Jan, CI; Lin, SC; Hu, WY; Chou, SH; Liu, CJ; Lo, JF (November 2009). "Tid1 functions as a tumour suppressor in head and neck squamous cell carcinoma". The Journal of pathology. 219 (3): 347–55. doi:10.1002/path.2604. PMID 19681071.
  9. ↑ 9.0 9.1 Sarkar S, Pollack BP, Lin KT, Kotenko SV, Cook JR, Lewis A, Pestka S (December 2001). "hTid-1, a human DnaJ protein, modulates the interferon signaling pathway". J. Biol. Chem. 276 (52): 49034–42. doi:10.1074/jbc.M103683200. PMID 11679576.
  10. ↑ Trentin GA, Yin X, Tahir S, Lhotak S, Farhang-Fallah J, Li Y, Rozakis-Adcock M (April 2001). "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. doi:10.1074/jbc.M009267200. PMID 11116152.

Further reading

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