| Structural highlights
Function
CK5P3_HUMAN Substrate adapter of E3 ligase complexes mediating ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to substrate proteins, and which is involved in various processes, such as ribosome recycling and reticulophagy (also called ER-phagy) (PubMed:23152784, PubMed:30635284, PubMed:32851973, PubMed:36121123, PubMed:36543799, PubMed:37595036, PubMed:38383785, PubMed:38383789). As part of the UREL complex, plays a key role in ribosome recycling by promoting 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:32851973, PubMed:37595036, PubMed:38383785, PubMed:38383789). Within the UREL complex, CDK5RAP3 acts as a substrate adapter that constrains UFL1 ligase activity to mono-ufmylate RPL26/uL24 at 'Lys-134' (PubMed:36121123, PubMed:38383785, PubMed:38383789). The UREL complex is also involved in reticulophagy in response to endoplasmic reticulum stress by promoting ufmylation of proteins such as CYB5R3, thereby promoting lysosomal degradation of ufmylated proteins (PubMed:36543799). Also acts as a regulator of transcription: negatively regulates NF-kappa-B-mediated gene transcription through the control of RELA phosphorylation (PubMed:17785205, PubMed:20228063). Also regulates mitotic G2/M transition checkpoint and mitotic G2 DNA damage checkpoint (PubMed:15790566, PubMed:19223857). Through its interaction with CDKN2A/ARF and MDM2 may induce MDM2-dependent p53/TP53 ubiquitination, stabilization and activation in the nucleus, thereby promoting G1 cell cycle arrest and inhibition of cell proliferation (PubMed:16173922). May also play a role in the rupture of the nuclear envelope during apoptosis (PubMed:23478299). May regulate MAPK14 activity by regulating its dephosphorylation by PPM1D/WIP1 (PubMed:21283629). Required for liver development (By similarity).[UniProtKB:Q99LM2][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] (Microbial infection) May be negatively regulated by hepatitis B virus large envelope protein mutant pre-s2 to promote mitotic entry.[16]
Publication Abstract from PubMed
Degradation of arrest peptides from endoplasmic reticulum (ER) translocon-bound 60S ribosomal subunits via the ribosome-associated quality control (ER-RQC) pathway requires covalent modification of RPL26/uL24 on 60S ribosomal subunits with UFM1. However, the underlying mechanism that coordinates the UFMylation and RQC pathways remains elusive. Structural analysis of ER-RQC intermediates revealed concomitant binding and direct interaction of the UFMylation and RQC machineries on the 60S. In the presence of an arrested peptidyl-transfer RNA, the RQC factor NEMF and the UFM1 E3 ligase (E3(UFM1)) form a direct interaction via the UFL1 subunit of E3(UFM1), and UFL1 adopts a conformation distinct from that previously observed for posttermination 60S. While this concomitant binding occurs on translocon-bound 60S, LTN1 recruitment and arrest peptide degradation require UFMylation-dependent 60S dissociation from the translocon. These data reveal a mechanism by which the UFMylation cycle orchestrates ER-RQC.
UFMylation orchestrates spatiotemporal coordination of RQC at the ER.,Penchev I, Gumbin S, Scavone F, Berninghausen O, Becker T, Kopito R, Beckmann R Sci Adv. 2025 May 2;11(18):eadv0435. doi: 10.1126/sciadv.adv0435. Epub 2025 May , 2. PMID:40315331[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Wang J, He X, Luo Y, Yarbrough WG. A novel ARF-binding protein (LZAP) alters ARF regulation of HDM2. Biochem J. 2006 Jan 15;393(Pt 2):489-501. PMID:16173922 doi:10.1042/BJ20050960
- ↑ Wang J, An H, Mayo MW, Baldwin AS, Yarbrough WG. LZAP, a putative tumor suppressor, selectively inhibits NF-kappaB. Cancer Cell. 2007 Sep;12(3):239-51. PMID:17785205 doi:10.1016/j.ccr.2007.07.002
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- ↑ Wu J, Lei G, Mei M, Tang Y, Li H. A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing Protein 1 (DDRGK1) and modulates NF-kappaB signaling. J Biol Chem. 2010 May 14;285(20):15126-15136. PMID:20228063 doi:10.1074/jbc.M110.110619
- ↑ An H, Lu X, Liu D, Yarbrough WG. LZAP inhibits p38 MAPK (p38) phosphorylation and activity by facilitating p38 association with the wild-type p53 induced phosphatase 1 (WIP1). PLoS One. 2011 Jan 24;6(1):e16427. PMID:21283629 doi:10.1371/journal.pone.0016427
- ↑ Zhang Y, Zhang M, Wu J, Lei G, Li H. Transcriptional regulation of the Ufm1 conjugation system in response to disturbance of the endoplasmic reticulum homeostasis and inhibition of vesicle trafficking. PLoS One. 2012;7(11):e48587. PMID:23152784 doi:10.1371/journal.pone.0048587
- ↑ Wu J, Jiang H, Luo S, Zhang M, Zhang Y, Sun F, Huang S, Li H. Caspase-mediated cleavage of C53/LZAP protein causes abnormal microtubule bundling and rupture of the nuclear envelope. Cell Res. 2013 May;23(5):691-704. PMID:23478299 doi:10.1038/cr.2013.36
- ↑ Yang R, Wang H, Kang B, Chen B, Shi Y, Yang S, Sun L, Liu Y, Xiao W, Zhang T, Yang J, Zhang Y, Zhu M, Xu P, Chang Y, Jia Y, Huang Y. CDK5RAP3, a UFL1 substrate adaptor, is crucial for liver development. Development. 2019 Jan 25;146(2):dev169235. PMID:30635284 doi:10.1242/dev.169235
- ↑ Stephani M, Picchianti L, Gajic A, Beveridge R, Skarwan E, Sanchez de Medina Hernandez V, Mohseni A, Clavel M, Zeng Y, Naumann C, Matuszkiewicz M, Turco E, Loefke C, Li B, Dürnberger G, Schutzbier M, Chen HT, Abdrakhmanov A, Savova A, Chia KS, Djamei A, Schaffner I, Abel S, Jiang L, Mechtler K, Ikeda F, Martens S, Clausen T, Dagdas Y. A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during stress. Elife. 2020 Aug 27;9:e58396. PMID:32851973 doi:10.7554/eLife.58396
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Lei Y, Liu H, Yang Y, Wang X, Ren N, Li B, Liu S, Cheng J, Fu X, Zhang J. Interaction of LHBs with C53 promotes hepatocyte mitotic entry: A novel mechanism for HBV-induced hepatocellular carcinoma. Oncol Rep. 2012 Jan;27(1):151-9. PMID:21971960 doi:10.3892/or.2011.1489
- ↑ Penchev I, Gumbin S, Scavone F, Berninghausen O, Becker T, Kopito R, Beckmann R. UFMylation orchestrates spatiotemporal coordination of RQC at the ER. Sci Adv. 2025 May 2;11(18):eadv0435. PMID:40315331 doi:10.1126/sciadv.adv0435
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