7w3n

Structural highlights

Disease

DDRGK_HUMAN Spondyloepimetaphyseal dysplasia, Shohat type. The disease is caused by variants affecting the gene represented in this entry.

Function

UFM1_HUMAN Ubiquitin-like modifier protein which binds to a number of target proteins, such as DDRGK1.^{[1] [2]} DDRGK_HUMAN Substrate adapter for ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to substrate proteins, which plays a key role in reticulophagy (also called ER-phagy) (PubMed:32160526). In response to endoplasmic reticulum stress, promotes recruitment of the E3 UFM1-protein ligase UFL1 to the endoplasmic reticulum membrane: in turn, UFL1 mediates ufmylation of proteins such as RPN1 and RPL26/uL24, promoting reticulophagy of endoplasmic reticulum sheets (PubMed:32160526). Ufmylation-dependent reticulophagy inhibits the unfolded protein response (UPR) by regulating ERN1/IRE1-alpha stability (PubMed:28128204, PubMed:32160526). Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis or inflammatory response (By similarity). Required for TRIP4 ufmylation, thereby regulating nuclear receptors-mediated. transcription (PubMed:25219498). May play a role in NF-kappa-B-mediated transcription through regulation of the phosphorylation and the degradation of NFKBIA, the inhibitor of NF-kappa-B (PubMed:23675531). Plays a role in cartilage development through SOX9, inhibiting the ubiquitin-mediated proteasomal degradation of this transcriptional regulator (PubMed:28263186).[UniProtKB:Q80WW9]^{[3] [4] [5] [6] [7]}

References

1. ↑ Komatsu M, Chiba T, Tatsumi K, Iemura S, Tanida I, Okazaki N, Ueno T, Kominami E, Natsume T, Tanaka K. A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. EMBO J. 2004 May 5;23(9):1977-86. Epub 2004 Apr 8. PMID:15071506 doi:http://dx.doi.org/10.1038/sj.emboj.7600205
2. ↑ Tatsumi K, Sou YS, Tada N, Nakamura E, Iemura S, Natsume T, Kang SH, Chung CH, Kasahara M, Kominami E, Yamamoto M, Tanaka K, Komatsu M. A novel type of E3 ligase for the Ufm1 conjugation system. J Biol Chem. 2010 Feb 19;285(8):5417-27. doi: 10.1074/jbc.M109.036814. Epub 2009 , Dec 14. PMID:20018847 doi:http://dx.doi.org/10.1074/jbc.M109.036814
3. ↑ Xi P, Ding D, Zhou J, Wang M, Cong YS. DDRGK1 regulates NF-kappaB activity by modulating IkappaBalpha stability. PLoS One. 2013 May 10;8(5):e64231. doi: 10.1371/journal.pone.0064231. Print 2013. PMID:23675531 doi:http://dx.doi.org/10.1371/journal.pone.0064231
4. ↑ Yoo HM, Kang SH, Kim JY, Lee JE, Seong MW, Lee SW, Ka SH, Sou YS, Komatsu M, Tanaka K, Lee ST, Noh DY, Baek SH, Jeon YJ, Chung CH. Modification of ASC1 by UFM1 is crucial for ERalpha transactivation and breast cancer development. Mol Cell. 2014 Oct 23;56(2):261-274. doi: 10.1016/j.molcel.2014.08.007. Epub 2014 , Sep 11. PMID:25219498 doi:http://dx.doi.org/10.1016/j.molcel.2014.08.007
5. ↑ Liu J, Wang Y, Song L, Zeng L, Yi W, Liu T, Chen H, Wang M, Ju Z, Cong YS. A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1alpha stability. Nat Commun. 2017 Jan 27;8:14186. doi: 10.1038/ncomms14186. PMID:28128204 doi:http://dx.doi.org/10.1038/ncomms14186
6. ↑ Egunsola AT, Bae Y, Jiang MM, Liu DS, Chen-Evenson Y, Bertin T, Chen S, Lu JT, Nevarez L, Magal N, Raas-Rothschild A, Swindell EC, Cohn DH, Gibbs RA, Campeau PM, Shohat M, Lee BH. Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia. J Clin Invest. 2017 Apr 3;127(4):1475-1484. doi: 10.1172/JCI90193. Epub 2017 Mar , 6. PMID:28263186 doi:http://dx.doi.org/10.1172/JCI90193
7. ↑ Liang JR, Lingeman E, Luong T, Ahmed S, Muhar M, Nguyen T, Olzmann JA, Corn JE. A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation. Cell. 2020 Mar 19;180(6):1160-1177.e20. doi: 10.1016/j.cell.2020.02.017. Epub , 2020 Mar 10. PMID:32160526 doi:http://dx.doi.org/10.1016/j.cell.2020.02.017