| Structural highlights
Function
UBD_HUMAN Ubiquitin-like protein modifier which can be covalently attached to target protein and subsequently leads to their degradation by the 26S proteasome, in a NUB1L-dependent manner. Probably functions as a survival factor. Conjugation ability activated by UBA6. Promotes the expression of the proteasome subunit beta type-9 (PSMB9/LMP2). Regulates TNF-alpha-induced and LPS-mediated activation of the central mediator of innate immunity NF-kappa-B by promoting TNF-alpha-mediated proteasomal degradation of ubiquitinated-I-kappa-B-alpha. Required for TNF-alpha-induced p65 nuclear translocation in renal tubular epithelial cells (RTECs). May be involved in dendritic cell (DC) maturation, the process by which immature dendritic cells differentiate into fully competent antigen-presenting cells that initiate T-cell responses. Mediates mitotic non-disjunction and chromosome instability, in long-term in vitro culture and cancers, by abbreviating mitotic phase and impairing the kinetochore localization of MAD2L1 during the prometaphase stage of the cell cycle. May be involved in the formation of aggresomes when proteasome is saturated or impaired. Mediates apoptosis in a caspase-dependent manner, especially in renal epithelium and tubular cells during renal diseases such as polycystic kidney disease and Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
FAT10 is a ubiquitin-like modifier that directly targets proteins for proteasomal degradation. Here, we report the high-resolution structures of the two individual ubiquitin-like domains (UBD) of FAT10 that are joined by a flexible linker. While the UBDs of FAT10 show the typical ubiquitin-fold, their surfaces are entirely different from each other and from ubiquitin explaining their unique binding specificities. Deletion of the linker abrogates FAT10-conjugation while its mutation blocks auto-FAT10ylation of the FAT10-conjugating enzyme USE1 but not bulk conjugate formation. FAT10- but not ubiquitin-mediated degradation is independent of the segregase VCP/p97 in the presence but not the absence of FAT10's unstructured N-terminal heptapeptide. Stabilization of the FAT10 UBDs strongly decelerates degradation suggesting that the intrinsic instability of FAT10 together with its disordered N-terminus enables the rapid, joint degradation of FAT10 and its substrates without the need for FAT10 de-conjugation and partial substrate unfolding.
The structure of the ubiquitin-like modifier FAT10 reveals an alternative targeting mechanism for proteasomal degradation.,Aichem A, Anders S, Catone N, Rossler P, Stotz S, Berg A, Schwab R, Scheuermann S, Bialas J, Schutz-Stoffregen MC, Schmidtke G, Peter C, Groettrup M, Wiesner S Nat Commun. 2018 Aug 20;9(1):3321. doi: 10.1038/s41467-018-05776-3. PMID:30127417[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hipp MS, Kalveram B, Raasi S, Groettrup M, Schmidtke G. FAT10, a ubiquitin-independent signal for proteasomal degradation. Mol Cell Biol. 2005 May;25(9):3483-91. PMID:15831455 doi:http://dx.doi.org/10.1128/MCB.25.9.3483-3491.2005
- ↑ Ross MJ, Wosnitzer MS, Ross MD, Granelli B, Gusella GL, Husain M, Kaufman L, Vasievich M, D'Agati VD, Wilson PD, Klotman ME, Klotman PE. Role of ubiquitin-like protein FAT10 in epithelial apoptosis in renal disease. J Am Soc Nephrol. 2006 Apr;17(4):996-1004. Epub 2006 Feb 22. PMID:16495380 doi:http://dx.doi.org/10.1681/ASN.2005070692
- ↑ Ren J, Kan A, Leong SH, Ooi LL, Jeang KT, Chong SS, Kon OL, Lee CG. FAT10 plays a role in the regulation of chromosomal stability. J Biol Chem. 2006 Apr 21;281(16):11413-21. Epub 2006 Feb 22. PMID:16495226 doi:http://dx.doi.org/10.1074/jbc.M507218200
- ↑ Chiu YH, Sun Q, Chen ZJ. E1-L2 activates both ubiquitin and FAT10. Mol Cell. 2007 Sep 21;27(6):1014-23. PMID:17889673 doi:http://dx.doi.org/10.1016/j.molcel.2007.08.020
- ↑ Kalveram B, Schmidtke G, Groettrup M. The ubiquitin-like modifier FAT10 interacts with HDAC6 and localizes to aggresomes under proteasome inhibition. J Cell Sci. 2008 Dec 15;121(Pt 24):4079-88. doi: 10.1242/jcs.035006. Epub 2008, Nov 25. PMID:19033385 doi:http://dx.doi.org/10.1242/jcs.035006
- ↑ Lukasiak S, Schiller C, Oehlschlaeger P, Schmidtke G, Krause P, Legler DF, Autschbach F, Schirmacher P, Breuhahn K, Groettrup M. Proinflammatory cytokines cause FAT10 upregulation in cancers of liver and colon. Oncogene. 2008 Oct 9;27(46):6068-74. doi: 10.1038/onc.2008.201. Epub 2008 Jun 23. PMID:18574467 doi:http://dx.doi.org/10.1038/onc.2008.201
- ↑ Schmidtke G, Kalveram B, Groettrup M. Degradation of FAT10 by the 26S proteasome is independent of ubiquitylation but relies on NUB1L. FEBS Lett. 2009 Feb 4;583(3):591-4. doi: 10.1016/j.febslet.2009.01.006. Epub 2009, Jan 21. PMID:19166848 doi:http://dx.doi.org/10.1016/j.febslet.2009.01.006
- ↑ Ebstein F, Lange N, Urban S, Seifert U, Kruger E, Kloetzel PM. Maturation of human dendritic cells is accompanied by functional remodelling of the ubiquitin-proteasome system. Int J Biochem Cell Biol. 2009 May;41(5):1205-15. doi:, 10.1016/j.biocel.2008.10.023. Epub 2008 Nov 5. PMID:19028597 doi:http://dx.doi.org/10.1016/j.biocel.2008.10.023
- ↑ Snyder A, Alsauskas Z, Gong P, Rosenstiel PE, Klotman ME, Klotman PE, Ross MJ. FAT10: a novel mediator of Vpr-induced apoptosis in human immunodeficiency virus-associated nephropathy. J Virol. 2009 Nov;83(22):11983-8. doi: 10.1128/JVI.00034-09. Epub 2009 Sep 2. PMID:19726511 doi:http://dx.doi.org/10.1128/JVI.00034-09
- ↑ Gong P, Canaan A, Wang B, Leventhal J, Snyder A, Nair V, Cohen CD, Kretzler M, D'Agati V, Weissman S, Ross MJ. The ubiquitin-like protein FAT10 mediates NF-kappaB activation. J Am Soc Nephrol. 2010 Feb;21(2):316-26. doi: 10.1681/ASN.2009050479. Epub 2009, Dec 3. PMID:19959714 doi:http://dx.doi.org/10.1681/ASN.2009050479
- ↑ Aichem A, Anders S, Catone N, Rossler P, Stotz S, Berg A, Schwab R, Scheuermann S, Bialas J, Schutz-Stoffregen MC, Schmidtke G, Peter C, Groettrup M, Wiesner S. The structure of the ubiquitin-like modifier FAT10 reveals an alternative targeting mechanism for proteasomal degradation. Nat Commun. 2018 Aug 20;9(1):3321. doi: 10.1038/s41467-018-05776-3. PMID:30127417 doi:http://dx.doi.org/10.1038/s41467-018-05776-3
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