2n9p

Structural highlights

Function

[RN126_HUMAN] E3 ubiquitin-protein ligase that regulates several biological processes through ubiquitination of various target proteins. Depending on the associated E2 ligase, mediates 'Lys-48'- and 'Lys-63'-linked polyubiquitination of substrates. Through their polyubiquitination, may play a role in the endosomal sorting and degradation of several membrane receptors including EGFR, FLT3, MET and CXCR4. May also be part of a BAG6-dependent quality control process ensuring that proteins of the secretory pathway that are mislocalized to the cytosol are degraded by the proteasome. May provide the ubiquitin ligase activity associated with the BAG6 complex and be responsible for ubiquitination of the mislocalized proteins and their targeting to the proteasome (PubMed:24981174). May also play a role in the endosomal recycling of IGF2R, the cation-independent mannose-6-phosphate receptor (PubMed:24275455). By ubiquitinating CDKN1A/p21 and targeting it for degradation, may also promote cell proliferation (PubMed:23026136). May monoubiquitinate AICDA (PubMed:23277564).[UniProtKB:Q91YL2]^{[1] [2] [3] [4]} [BAG6_HUMAN] Chaperone that plays a key role in various processes such as apoptosis, insertion of tail-anchored (TA) membrane proteins to the endoplasmic reticulum membrane and regulation of chromatin. Acts in part by regulating stability of proteins and their degradation by the proteasome. Participates in endoplasmic reticulum stress-induced apoptosis via its interaction with AIFM1/AIF by regulating AIFM1/AIF stability and preventing its degradation. Also required during spermatogenesis for synaptonemal complex assembly via its interaction with HSPA2, by inhibiting polyubiquitination and subsequent proteasomal degradation of HSPA2. Required for selective ubiquitin-mediated degradation of defective nascent chain polypeptides by the proteasome. In this context, may play a role in immuno-proteasomes to generate antigenic peptides via targeted degradation, thereby playing a role in antigen presentation in immune response. Key component of the BAG6/BAT3 complex, a cytosolic multiprotein complex involved in the post-translational delivery of tail-anchored (TA) membrane proteins to the endoplasmic reticulum membrane. TA membrane proteins, also named type II transmembrane proteins, contain a single C-terminal transmembrane region. BAG6/BAT3 acts by facilitating TA membrane proteins capture by ASNA1/TRC40: it is recruited to ribosomes synthesizing membrane proteins, interacts with the transmembrane region of newly released TA proteins and transfers them to ASNA1/TRC40 for targeting to the endoplasmic reticulum membrane.^{[5] [6] [7] [8] [9] [10] [11]} Involved in DNA damage-induced apoptosis: following DNA damage, accumulates in the nucleus and forms a complex with p300/EP300, enhancing p300/EP300-mediated p53/TP53 acetylation leading to increase p53/TP53 transcriptional activity. When nuclear, may also act as a component of some chromatin regulator complex that regulates histone 3 'Lys-4' dimethylation (H3K4me2).^{[12] [13] [14] [15] [16] [17] [18]} Can be released from tumor and dendritic cells in membrane vesicles or exosomes, and engage NCR3 thereby promoting natural killer cell (NK) activation and cytotoxicity.^{[19] [20] [21] [22] [23] [24] [25]}

See Also

• BAG family proteins 3D structures
• Ubiquitin protein ligase 3D structures

References

1. ↑ Delker RK, Zhou Y, Strikoudis A, Stebbins CE, Papavasiliou FN. Solubility-based genetic screen identifies RING finger protein 126 as an E3 ligase for activation-induced cytidine deaminase. Proc Natl Acad Sci U S A. 2013 Jan 15;110(3):1029-34. doi:, 10.1073/pnas.1214538110. Epub 2012 Dec 31. PMID:23277564 doi:http://dx.doi.org/10.1073/pnas.1214538110
2. ↑ Smith CJ, McGlade CJ. The ubiquitin ligase RNF126 regulates the retrograde sorting of the cation-independent mannose 6-phosphate receptor. Exp Cell Res. 2014 Jan 15;320(2):219-32. doi: 10.1016/j.yexcr.2013.11.013. Epub, 2013 Nov 23. PMID:24275455 doi:http://dx.doi.org/10.1016/j.yexcr.2013.11.013
3. ↑ Rodrigo-Brenni MC, Gutierrez E, Hegde RS. Cytosolic quality control of mislocalized proteins requires RNF126 recruitment to Bag6. Mol Cell. 2014 Jul 17;55(2):227-37. doi: 10.1016/j.molcel.2014.05.025. Epub 2014 , Jun 26. PMID:24981174 doi:http://dx.doi.org/10.1016/j.molcel.2014.05.025
4. ↑ Zhi X, Zhao D, Wang Z, Zhou Z, Wang C, Chen W, Liu R, Chen C. E3 ubiquitin ligase RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation. Cancer Res. 2013 Jan 1;73(1):385-94. doi: 10.1158/0008-5472.CAN-12-0562. Epub, 2012 Oct 1. PMID:23026136 doi:http://dx.doi.org/10.1158/0008-5472.CAN-12-0562
5. ↑ Wu YH, Shih SF, Lin JY. Ricin triggers apoptotic morphological changes through caspase-3 cleavage of BAT3. J Biol Chem. 2004 Apr 30;279(18):19264-75. Epub 2004 Feb 11. PMID:14960581 doi:http://dx.doi.org/10.1074/jbc.M307049200
6. ↑ Sasaki T, Gan EC, Wakeham A, Kornbluth S, Mak TW, Okada H. HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53. Genes Dev. 2007 Apr 1;21(7):848-61. PMID:17403783 doi:http://dx.doi.org/10.1101/gad.1534107
7. ↑ Pogge von Strandmann E, Simhadri VR, von Tresckow B, Sasse S, Reiners KS, Hansen HP, Rothe A, Boll B, Simhadri VL, Borchmann P, McKinnon PJ, Hallek M, Engert A. Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity. 2007 Dec;27(6):965-74. Epub 2007 Dec 6. PMID:18055229 doi:http://dx.doi.org/10.1016/j.immuni.2007.10.010
8. ↑ Nguyen P, Bar-Sela G, Sun L, Bisht KS, Cui H, Kohn E, Feinberg AP, Gius D. BAT3 and SET1A form a complex with CTCFL/BORIS to modulate H3K4 histone dimethylation and gene expression. Mol Cell Biol. 2008 Nov;28(21):6720-9. Epub 2008 Sep 2. PMID:18765639 doi:http://dx.doi.org/MCB.00568-08
9. ↑ Simhadri VR, Reiners KS, Hansen HP, Topolar D, Simhadri VL, Nohroudi K, Kufer TA, Engert A, Pogge von Strandmann E. Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function. PLoS One. 2008;3(10):e3377. doi: 10.1371/journal.pone.0003377. Epub 2008 Oct 13. PMID:18852879 doi:10.1371/journal.pone.0003377
10. ↑ Leznicki P, Clancy A, Schwappach B, High S. Bat3 promotes the membrane integration of tail-anchored proteins. J Cell Sci. 2010 Jul 1;123(Pt 13):2170-8. doi: 10.1242/jcs.066738. Epub 2010 Jun , 1. PMID:20516149 doi:http://dx.doi.org/10.1242/jcs.066738
11. ↑ Mariappan M, Li X, Stefanovic S, Sharma A, Mateja A, Keenan RJ, Hegde RS. A ribosome-associating factor chaperones tail-anchored membrane proteins. Nature. 2010 Aug 26;466(7310):1120-4. doi: 10.1038/nature09296. Epub 2010 Aug 1. PMID:20676083 doi:http://dx.doi.org/10.1038/nature09296
12. ↑ Wu YH, Shih SF, Lin JY. Ricin triggers apoptotic morphological changes through caspase-3 cleavage of BAT3. J Biol Chem. 2004 Apr 30;279(18):19264-75. Epub 2004 Feb 11. PMID:14960581 doi:http://dx.doi.org/10.1074/jbc.M307049200
13. ↑ Sasaki T, Gan EC, Wakeham A, Kornbluth S, Mak TW, Okada H. HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53. Genes Dev. 2007 Apr 1;21(7):848-61. PMID:17403783 doi:http://dx.doi.org/10.1101/gad.1534107
14. ↑ Pogge von Strandmann E, Simhadri VR, von Tresckow B, Sasse S, Reiners KS, Hansen HP, Rothe A, Boll B, Simhadri VL, Borchmann P, McKinnon PJ, Hallek M, Engert A. Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity. 2007 Dec;27(6):965-74. Epub 2007 Dec 6. PMID:18055229 doi:http://dx.doi.org/10.1016/j.immuni.2007.10.010
15. ↑ Nguyen P, Bar-Sela G, Sun L, Bisht KS, Cui H, Kohn E, Feinberg AP, Gius D. BAT3 and SET1A form a complex with CTCFL/BORIS to modulate H3K4 histone dimethylation and gene expression. Mol Cell Biol. 2008 Nov;28(21):6720-9. Epub 2008 Sep 2. PMID:18765639 doi:http://dx.doi.org/MCB.00568-08
16. ↑ Simhadri VR, Reiners KS, Hansen HP, Topolar D, Simhadri VL, Nohroudi K, Kufer TA, Engert A, Pogge von Strandmann E. Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function. PLoS One. 2008;3(10):e3377. doi: 10.1371/journal.pone.0003377. Epub 2008 Oct 13. PMID:18852879 doi:10.1371/journal.pone.0003377
17. ↑ Leznicki P, Clancy A, Schwappach B, High S. Bat3 promotes the membrane integration of tail-anchored proteins. J Cell Sci. 2010 Jul 1;123(Pt 13):2170-8. doi: 10.1242/jcs.066738. Epub 2010 Jun , 1. PMID:20516149 doi:http://dx.doi.org/10.1242/jcs.066738
18. ↑ Mariappan M, Li X, Stefanovic S, Sharma A, Mateja A, Keenan RJ, Hegde RS. A ribosome-associating factor chaperones tail-anchored membrane proteins. Nature. 2010 Aug 26;466(7310):1120-4. doi: 10.1038/nature09296. Epub 2010 Aug 1. PMID:20676083 doi:http://dx.doi.org/10.1038/nature09296
19. ↑ Wu YH, Shih SF, Lin JY. Ricin triggers apoptotic morphological changes through caspase-3 cleavage of BAT3. J Biol Chem. 2004 Apr 30;279(18):19264-75. Epub 2004 Feb 11. PMID:14960581 doi:http://dx.doi.org/10.1074/jbc.M307049200
20. ↑ Sasaki T, Gan EC, Wakeham A, Kornbluth S, Mak TW, Okada H. HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53. Genes Dev. 2007 Apr 1;21(7):848-61. PMID:17403783 doi:http://dx.doi.org/10.1101/gad.1534107
21. ↑ Pogge von Strandmann E, Simhadri VR, von Tresckow B, Sasse S, Reiners KS, Hansen HP, Rothe A, Boll B, Simhadri VL, Borchmann P, McKinnon PJ, Hallek M, Engert A. Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity. 2007 Dec;27(6):965-74. Epub 2007 Dec 6. PMID:18055229 doi:http://dx.doi.org/10.1016/j.immuni.2007.10.010
22. ↑ Nguyen P, Bar-Sela G, Sun L, Bisht KS, Cui H, Kohn E, Feinberg AP, Gius D. BAT3 and SET1A form a complex with CTCFL/BORIS to modulate H3K4 histone dimethylation and gene expression. Mol Cell Biol. 2008 Nov;28(21):6720-9. Epub 2008 Sep 2. PMID:18765639 doi:http://dx.doi.org/MCB.00568-08
23. ↑ Simhadri VR, Reiners KS, Hansen HP, Topolar D, Simhadri VL, Nohroudi K, Kufer TA, Engert A, Pogge von Strandmann E. Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function. PLoS One. 2008;3(10):e3377. doi: 10.1371/journal.pone.0003377. Epub 2008 Oct 13. PMID:18852879 doi:10.1371/journal.pone.0003377
24. ↑ Leznicki P, Clancy A, Schwappach B, High S. Bat3 promotes the membrane integration of tail-anchored proteins. J Cell Sci. 2010 Jul 1;123(Pt 13):2170-8. doi: 10.1242/jcs.066738. Epub 2010 Jun , 1. PMID:20516149 doi:http://dx.doi.org/10.1242/jcs.066738
25. ↑ Mariappan M, Li X, Stefanovic S, Sharma A, Mateja A, Keenan RJ, Hegde RS. A ribosome-associating factor chaperones tail-anchored membrane proteins. Nature. 2010 Aug 26;466(7310):1120-4. doi: 10.1038/nature09296. Epub 2010 Aug 1. PMID:20676083 doi:http://dx.doi.org/10.1038/nature09296
26. ↑ Krysztofinska EM, Martinez-Lumbreras S, Thapaliya A, Evans NJ, High S, Isaacson RL. Structural and functional insights into the E3 ligase, RNF126. Sci Rep. 2016 May 19;6:26433. doi: 10.1038/srep26433. PMID:27193484 doi:http://dx.doi.org/10.1038/srep26433