| Structural highlights
Function
UFL1_HUMAN E3 protein ligase that mediates ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to lysine residues on target proteins, and which plays a key role in various processes, such as ribosome recycling, response to DNA damage, interferon response or reticulophagy (also called ER-phagy) (PubMed:20018847, PubMed:20164180, PubMed:20228063, PubMed:25219498, PubMed:27351204, PubMed:30626644, PubMed:30783677, PubMed:32160526, PubMed:32807901, PubMed:35394863, PubMed:36121123, PubMed:36543799, PubMed:36893266, PubMed:37036982, PubMed:37311461, PubMed:37595036, PubMed:37795761, PubMed:38377992, PubMed:38383785, PubMed:38383789). Catalyzes ufmylation of many protein, such as CD274/PD-L1, CDK5RAP3, CYB5R3, DDRGK1, EIF6, histone H4, MRE11, P4HB, PDCD1/PD-1, TRIP4, RPN1, RPS20/uS10, RPL10/uL16, RPL26/uL24, SYVN1/HRD1 and TP53/p53 (PubMed:20018847, PubMed:20531390, PubMed:25219498, PubMed:30783677, PubMed:30886146, PubMed:32160526, PubMed:35753586, PubMed:36543799, PubMed:36893266, PubMed:37036982, PubMed:37595036, PubMed:37795761, PubMed:38383785, PubMed:38383789). As part of the UREL complex, plays a key role in ribosome recycling by catalyzing mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome (PubMed:38383785, PubMed:38383789). Ufmylation of RPL26/uL24 occurs on free 60S ribosomes following ribosome dissociation: it weakens the junction between post-termination 60S subunits and SEC61 translocons, promoting release and recycling of the large ribosomal subunit from the endoplasmic reticulum membrane (PubMed:38383785, PubMed:38383789). Ufmylation of RPL26/uL24 and subsequent 60S ribosome recycling either take place after normal termination of translation or after ribosome stalling during cotranslational translocation at the endoplasmic reticulum (PubMed:37036982, PubMed:37595036, PubMed:38383785, PubMed:38383789). Involved in reticulophagy in response to endoplasmic reticulum stress by mediating ufmylation of proteins such as CYB5R3 and RPN1, thereby promoting lysosomal degradation of ufmylated proteins (PubMed:23152784, PubMed:32160526, PubMed:36543799). Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis, blood vessel morphogenesis or inflammatory response (PubMed:32050156). Mediates ufmylation of DDRGK1 and CDK5RAP3; the role of these modifications is however unclear: as both DDRGK1 and CDK5RAP3 act as substrate adapters for ufmylation, it is uncertain whether ufmylation of these proteins is, a collateral effect or is required for ufmylation (PubMed:20018847, PubMed:20531390). Acts as a negative regulator of T-cell activation by mediating ufmylation and stabilization of PDCD1/PD-1 (PubMed:38377992). Also involved in the response to DNA damage: recruited to double-strand break sites following DNA damage and mediates monoufmylation of histone H4 and ufmylation of MRE11 (PubMed:30783677, PubMed:30886146). Mediates ufmylation of TP53/p53, promoting its stability (PubMed:32807901). Catalyzes ufmylation of TRIP4, thereby playing a role in nuclear receptor-mediated transcription (PubMed:25219498). Required for hematopoietic stem cell function and hematopoiesis (By similarity).[UniProtKB:Q8CCJ3][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25]
Publication Abstract from PubMed
Stalled ribosomes at the endoplasmic reticulum (ER) are covalently modified with the ubiquitin-like protein UFM1 on the 60S ribosomal subunit protein RPL26 (also known as uL24)(1,2). This modification, which is known as UFMylation, is orchestrated by the UFM1 ribosome E3 ligase (UREL) complex, comprising UFL1, UFBP1 and CDK5RAP3 (ref. (3)). However, the catalytic mechanism of UREL and the functional consequences of UFMylation are unclear. Here we present cryo-electron microscopy structures of UREL bound to 60S ribosomes, revealing the basis of its substrate specificity. UREL wraps around the 60S subunit to form a C-shaped clamp architecture that blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other. A UFL1 loop inserts into and remodels the peptidyl transferase centre. These features of UREL suggest a crucial function for UFMylation in the release and recycling of stalled or terminated ribosomes from the ER membrane. In the absence of functional UREL, 60S-SEC61 translocon complexes accumulate at the ER membrane, demonstrating that UFMylation is necessary for releasing SEC61 from 60S subunits. Notably, this release is facilitated by a functional switch of UREL from a 'writer' to a 'reader' module that recognizes its product-UFMylated 60S ribosomes. Collectively, we identify a fundamental role for UREL in dissociating 60S subunits from the SEC61 translocon and the basis for UFMylation in regulating protein homeostasis at the ER.
The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons.,Makhlouf L, Peter JJ, Magnussen HM, Thakur R, Millrine D, Minshull TC, Harrison G, Varghese J, Lamoliatte F, Foglizzo M, Macartney T, Calabrese AN, Zeqiraj E, Kulathu Y Nature. 2024 Mar;627(8003):437-444. doi: 10.1038/s41586-024-07093-w. Epub 2024 , Feb 21. PMID:38383789[26]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ 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
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- ↑ Walczak CP, Leto DE, Zhang L, Riepe C, Muller RY, DaRosa PA, Ingolia NT, Elias JE, Kopito RR. Ribosomal protein RPL26 is the principal target of UFMylation. Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1299-1308. doi:, 10.1073/pnas.1816202116. Epub 2019 Jan 9. PMID:30626644 doi:http://dx.doi.org/10.1073/pnas.1816202116
- ↑ Wang Z, Gong Y, Peng B, Shi R, Fan D, Zhao H, Zhu M, Zhang H, Lou Z, Zhou J, Zhu WG, Cong YS, Xu X. MRE11 UFMylation promotes ATM activation. Nucleic Acids Res. 2019 May 7;47(8):4124-4135. PMID:30783677 doi:10.1093/nar/gkz110
- ↑ Qin B, Yu J, Nowsheen S, Wang M, Tu X, Liu T, Li H, Wang L, Lou Z. UFL1 promotes histone H4 ufmylation and ATM activation. Nat Commun. 2019 Mar 18;10(1):1242. PMID:30886146 doi:10.1038/s41467-019-09175-0
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- ↑ 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
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- ↑ Snider DL, Park M, Murphy KA, Beachboard DC, Horner SM. Signaling from the RNA sensor RIG-I is regulated by ufmylation. Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2119531119. PMID:35394863 doi:10.1073/pnas.2119531119
- ↑ Zhu J, Ma X, Jing Y, Zhang G, Zhang D, Mao Z, Ma X, Liu H, Chen F. P4HB UFMylation regulates mitochondrial function and oxidative stress. Free Radic Biol Med. 2022 Aug 1;188:277-286. PMID:35753586 doi:10.1016/j.freeradbiomed.2022.06.237
- ↑ Peter JJ, Magnussen HM, DaRosa PA, Millrine D, Matthews SP, Lamoliatte F, Sundaramoorthy R, Kopito RR, Kulathu Y. A non-canonical scaffold-type E3 ligase complex mediates protein UFMylation. EMBO J. 2022 Nov 2;41(21):e111015. PMID:36121123 doi:10.15252/embj.2022111015
- ↑ Ishimura R, El-Gowily AH, Noshiro D, Komatsu-Hirota S, Ono Y, Shindo M, Hatta T, Abe M, Uemura T, Lee-Okada HC, Mohamed TM, Yokomizo T, Ueno T, Sakimura K, Natsume T, Sorimachi H, Inada T, Waguri S, Noda NN, Komatsu M. The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3. Nat Commun. 2022 Dec 21;13(1):7857. PMID:36543799 doi:10.1038/s41467-022-35501-0
- ↑ Zhou J, Ma X, He X, Chen B, Yuan J, Jin Z, Li L, Wang Z, Xiao Q, Cai Y, Zou Y, Cong YS. Dysregulation of PD-L1 by UFMylation imparts tumor immune evasion and identified as a potential therapeutic target. Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2215732120. PMID:36893266 doi:10.1073/pnas.2215732120
- ↑ Scavone F, Gumbin SC, Da Rosa PA, Kopito RR. RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum. Proc Natl Acad Sci U S A. 2023 Apr 18;120(16):e2220340120. PMID:37036982 doi:10.1073/pnas.2220340120
- ↑ Yiu SPT, Zerbe C, Vanderwall D, Huttlin EL, Weekes MP, Gewurz BE. An Epstein-Barr virus protein interaction map reveals NLRP3 inflammasome evasion via MAVS UFMylation. Mol Cell. 2023 Jul 6;83(13):2367-2386.e15. PMID:37311461 doi:10.1016/j.molcel.2023.05.018
- ↑ Ishimura R, Ito S, Mao G, Komatsu-Hirota S, Inada T, Noda NN, Komatsu M. Mechanistic insights into the roles of the UFM1 E3 ligase complex in ufmylation and ribosome-associated protein quality control. Sci Adv. 2023 Aug 18;9(33):eadh3635. PMID:37595036 doi:10.1126/sciadv.adh3635
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- ↑ He C, Xing X, Chen HY, Gao M, Shi J, Xiang B, Xiao X, Sun Y, Yu H, Xu G, Yao Y, Xie Z, Xing Y, Budiarto BR, Chen SY, Gao Y, Lee YR, Zhang J. UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity. Mol Cell. 2024 Mar 21;84(6):1120-1138.e8. PMID:38377992 doi:10.1016/j.molcel.2024.01.024
- ↑ DaRosa PA, Penchev I, Gumbin SC, Scavone F, Wąchalska M, Paulo JA, Ordureau A, Peter JJ, Kulathu Y, Harper JW, Becker T, Beckmann R, Kopito RR. UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER. Nature. 2024 Mar;627(8003):445-452. PMID:38383785 doi:10.1038/s41586-024-07073-0
- ↑ Makhlouf L, Peter JJ, Magnussen HM, Thakur R, Millrine D, Minshull TC, Harrison G, Varghese J, Lamoliatte F, Foglizzo M, Macartney T, Calabrese AN, Zeqiraj E, Kulathu Y. The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons. Nature. 2024 Mar;627(8003):437-444. PMID:38383789 doi:10.1038/s41586-024-07093-w
- ↑ Makhlouf L, Peter JJ, Magnussen HM, Thakur R, Millrine D, Minshull TC, Harrison G, Varghese J, Lamoliatte F, Foglizzo M, Macartney T, Calabrese AN, Zeqiraj E, Kulathu Y. The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons. Nature. 2024 Mar;627(8003):437-444. PMID:38383789 doi:10.1038/s41586-024-07093-w
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