Ribosome-associated quality control

Abaeva IS, Bulakhov AG, Hellen CUT, Pestova TV. The ribosome-associated quality control factor TCF25 imposes K48 specificity on Listerin-mediated ubiquitination of nascent chains by binding and specifically orienting the acceptor ubiquitin. Genes Dev. 2025 May 02;39(9-10):617–33. PMID: 40169231; PMCID: PMC12047659.; Ford PW, Narasimhan M, Bennett EJ. Ubiquitin-dependent translation control mechanisms: Degradation and beyond. Cell Reports. 2024 Dec;43(12):115050. doi: 10.1016/j.celrep.2024.115050.; McGirr T, Onar O, Jafarnejad SM. Dysregulated ribosome quality control in human diseases. FEBS J. 2025 Mar;292(5):936–59. PMID: 38949989; PMCID: PMC11880988.; Miscicka A, Bulakhov AG, Kuroha K, Zinoviev A, Hellen CUT, Pestova TV. Ribosomal collision is not a prerequisite for ZNF598-mediated ribosome ubiquitination and disassembly of ribosomal complexes by ASCC. Nucleic Acids Res. 2024 May 08;52(8):4627–43. PMID: 38366554; PMCID: PMC11077048.; Patil PR, Burroughs AM, Misra M, Cerullo F, Costas-Insua C, Hung HC, Dikic I, Aravind L, Joazeiro CAP. Mechanism and evolutionary origins of alanine-tail C-degron recognition by E3 ligases Pirh2 and CRL2-KLHDC10. Cell Rep. 2023 Sep 26;42(9):113100. PMID: 37676773; PMCID: PMC10591846.; Wang X, Li Y, Yan X, Yang Q, Zhang B, Zhang Y, Yuan X, Jiang C, Chen D, Liu Q, Liu T, Mi W, Yu Y, Dong C. Recognition of an Ala-rich C-degron by the E3 ligase Pirh2. Nat Commun. 2023 Apr 29;14(1):2474. PMID: 37120596; PMCID: PMC10148881.; Williams C, Dong KC, Arkinson C, Martin A. The Ufd1 cofactor determines the linkage specificity of polyubiquitin chain engagement by the AAA+ ATPase Cdc48. Molecular Cell. 2023 Mar;83(5):759–769.e7. doi: 10.1016/j.molcel.2023.01.016.; Best K, Ikeuchi K, Kater L, Best D, Musial J, Matsuo Y, Berninghausen O, Becker T, Inada T, Beckmann R. Structural basis for clearing of ribosome collisions by the RQT complex. Nat Commun. 2023 Feb 17;14(1):921. PMID: 36801861; PMCID: PMC9938168.; Tesina P, Ebine S, Buschauer R, Thoms M, Matsuo Y, Inada T, Beckmann R. Molecular basis of eIF5A-dependent CAT tailing in eukaryotic ribosome-associated quality control. Mol Cell. 2023 Feb 16;83(4):607–621.e4. doi: 10.1016/j.molcel.2023.01.020. PMID: 36804914.; Meyer H, van den Boom J. Targeting of client proteins to the VCP/p97/Cdc48 unfolding machine. Front Mol Biosci. 2023;10():1142989. PMID: 36825201; PMCID: PMC9941556.; Matsuo Y, Uchihashi T, Inada T. Decoding of the ubiquitin code for clearance of colliding ribosomes by the RQT complex. Nat Commun. 2023 Jan 10;14(1):79. PMID: 36627279; PMCID: PMC9831982.; Eisenack TJ, Trentini DB. Ending a bad start: Triggers and mechanisms of co-translational protein degradation. Front Mol Biosci. 2022;9():1089825. PMID: 36660423; PMCID: PMC9846516.; Narita M, Denk T, Matsuo Y, Sugiyama T, Kikuguchi C, Ito S, Sato N, Suzuki T, Hashimoto S, Machová I, Tesina P, Beckmann R, Inada T. A distinct mammalian disome collision interface harbors K63-linked polyubiquitination of uS10 to trigger hRQT-mediated subunit dissociation. Nature Communications. 2022 Oct 27;13(1):6411. doi: 10.1038/s41467-022-34097-9.; Filbeck S, Cerullo F, Pfeffer S, Joazeiro CAP. Ribosome-associated quality-control mechanisms from bacteria to humans. Molecular Cell. 2022 Apr;82(8):1451–66. doi: 10.1016/j.molcel.2022.03.038.; Mishra R, Bansal A, Mishra A. LISTERIN E3 Ubiquitin Ligase and Ribosome-Associated Quality Control (RQC) Mechanism. Mol Neurobiol. 2021 Dec;58(12):6593–609. doi: 10.1007/s12035-021-02564-x. PMID: 34590243.; Thrun A, Garzia A, Kigoshi-Tansho Y, Patil PR, Umbaugh CS, Dallinger T, Liu J, Kreger S, Patrizi A, Cox GA, Tuschl T, Joazeiro CAP. Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing. Molecular Cell. 2021 May;81(10):2112–2122.e7. doi: 10.1016/j.molcel.2021.03.004.; Udagawa T, Seki M, Okuyama T, Adachi S, Natsume T, Noguchi T, Matsuzawa A, Inada T. Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Morphogenesis and Cell Survival. Cell Rep. 2021 Jan 05;34(1):108599. doi: 10.1016/j.celrep.2020.108599. PMID: 33406423.; Hickey KL, Dickson K, Cogan JZ, Replogle JM, Schoof M, D’Orazio KN, Sinha NK, Hussmann JA, Jost M, Frost A, Green R, Weissman JS, Kostova KK. GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control. Molecular Cell. 2020 Sep;79(6):950–962.e6. doi: 10.1016/j.molcel.2020.07.007.; Juszkiewicz S, Speldewinde SH, Wan L, Svejstrup JQ, Hegde RS. The ASC-1 Complex Disassembles Collided Ribosomes. Molecular Cell. 2020 Aug;79(4):603–614.e8. doi: 10.1016/j.molcel.2020.06.006.; Sinha NK, Ordureau A, Best K, Saba JA, Zinshteyn B, Sundaramoorthy E, Fulzele A, Garshott DM, Denk T, Thoms M, Paulo JA, Harper JW, Bennett EJ, Beckmann R, Green R. EDF1 coordinates cellular responses to ribosome collisions. Elife. 2020 Aug 03;9(). PMID: 32744497; PMCID: PMC7486125.; Juszkiewicz S, Slodkowicz G, Lin Z, Freire-Pritchett P, Peak-Chew S, Hegde RS. Author response: Ribosome collisions trigger cis-acting feedback inhibition of translation initiation. 2020 Jul 09;(). doi: 10.7554/elife.60038.sa2.; Sitron CS, Brandman O. Detection and Degradation of Stalled Nascent Chains via Ribosome-Associated Quality Control. Annu. Rev. Biochem. 2020 Jun 20;89(1):417–42. doi: 10.1146/annurev-biochem-013118-110729.; Meyer C, Garzia A, Morozov P, Molina H, Tuschl T. The G3BP1-Family-USP10 Deubiquitinase Complex Rescues Ubiquitinated 40S Subunits of Ribosomes Stalled in Translation from Lysosomal Degradation. Mol Cell. 2020 Mar 19;77(6):1193–1205.e5. doi: 10.1016/j.molcel.2019.12.024. PMID: 31981475.; Hashimoto S, Sugiyama T, Yamazaki R, Nobuta R, Inada T. Identification of a novel trigger complex that facilitates ribosome-associated quality control in mammalian cells. Scientific Reports. 2020 Feb 25;10(1):3422. doi: 10.1038/s41598-020-60241-w.; Garshott DM, Sundaramoorthy E, Leonard M, Bennett EJ. Author response: Distinct regulatory ribosomal ubiquitylation events are reversible and hierarchically organized. 2020 Jan 29;(). doi: 10.7554/elife.54023.sa2.; Sato Y, Tsuchiya H, Yamagata A, Okatsu K, Tanaka K, Saeki Y, Fukai S. Structural insights into ubiquitin recognition and Ufd1 interaction of Npl4. Nature Communications. 2019 Dec 13;10(1):5708. doi: 10.1038/s41467-019-13697-y.; Su T, Izawa T, Thoms M, Yamashita Y, Cheng J, Berninghausen O, Hartl FU, Inada T, Neupert W, Beckmann R. Structure and function of Vms1 and Arb1 in RQC and mitochondrial proteome homeostasis. Nature. 2019 Jun;570(7762):538–42. doi: 10.1038/s41586-019-1307-z. PMID: 31189955.; Yip MCJ, Keszei AFA, Feng Q, Chu V, McKenna MJ, Shao S. Mechanism for recycling tRNAs on stalled ribosomes. Nature Structural & Molecular Biology. 2019 Apr 22;26(5):343–9. doi: 10.1038/s41594-019-0211-4.; Olszewski MM, Williams C, Dong KC, Martin A. The Cdc48 unfoldase prepares well-folded protein substrates for degradation by the 26S proteasome. Communications Biology. 2019 Jan 21;2(1):29. doi: 10.1038/s42003-019-0283-z.; Ikeuchi K, Tesina P, Matsuo Y, Sugiyama T, Cheng J, Saeki Y, Tanaka K, Becker T, Beckmann R, Inada T. Collided ribosomes form a unique structural interface to induce Hel2-driven quality control pathways. The EMBO Journal. 2019 Jan 04;38(5). doi: 10.15252/embj.2018100276.; Juszkiewicz S, Chandrasekaran V, Lin Z, Kraatz S, Ramakrishnan V, Hegde RS. ZNF598 Is a Quality Control Sensor of Collided Ribosomes. Molecular Cell. 2018 Nov;72(3):469–481.e7. doi: 10.1016/j.molcel.2018.08.037.; Kuroha K, Zinoviev A, Hellen CUT, Pestova TV. Release of Ubiquitinated and Non-ubiquitinated Nascent Chains from Stalled Mammalian Ribosomal Complexes by ANKZF1 and Ptrh1. Molecular Cell. 2018 Oct;72(2):286–302.e8. doi: 10.1016/j.molcel.2018.08.022.; Verma R, Reichermeier KM, Burroughs AM, Oania RS, Reitsma JM, Aravind L, Deshaies RJ. Vms1 and ANKZF1 peptidyl-tRNA hydrolases release nascent chains from stalled ribosomes. Nature. 2018 Apr 09;557(7705):446–51. doi: 10.1038/s41586-018-0022-5.; Joazeiro CAP. Ribosomal Stalling During Translation: Providing Substrates for Ribosome-Associated Protein Quality Control. Annu Rev Cell Dev Biol. 2017 Oct 06;33():343–68. doi: 10.1146/annurev-cellbio-111315-125249. PMID: 28715909.; Matsuo Y, Ikeuchi K, Saeki Y, Iwasaki S, Schmidt C, Udagawa T, Sato F, Tsuchiya H, Becker T, Tanaka K, Ingolia NT, Beckmann R, Inada T. Ubiquitination of stalled ribosome triggers ribosome-associated quality control. Nature Communications. 2017 Jul 31;8(1):159. doi: 10.1038/s41467-017-00188-1.; Kostova KK, Hickey KL, Osuna BA, Hussmann JA, Frost A, Weinberg DE, Weissman JS. CAT-tailing as a fail-safe mechanism for efficient degradation of stalled nascent polypeptides. Science. 2017 Jul 28;357(6349):414–7. PMID: 28751611; PMCID: PMC5673106.; Osuna BA, Howard CJ, KC S, Frost A, Weinberg DE. Author response: In vitro analysis of RQC activities provides insights into the mechanism and function of CAT tailing. 2017 Jul 09;(). doi: 10.7554/elife.27949.016.; Garzia A, Jafarnejad SM, Meyer C, Chapat C, Gogakos T, Morozov P, Amiri M, Shapiro M, Molina H, Tuschl T, Sonenberg N. The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs. Nature Communications. 2017 Jul 07;8(1):16056. doi: 10.1038/ncomms16056.; Tsuchiya H, Ohtake F, Arai N, Kaiho A, Yasuda S, Tanaka K, Saeki Y. In Vivo Ubiquitin Linkage-type Analysis Reveals that the Cdc48-Rad23/Dsk2 Axis Contributes to K48-Linked Chain Specificity of the Proteasome. Mol Cell. 2017 May 18;66(4):488–502.e7. doi: 10.1016/j.molcel.2017.04.024. PMID: 28525741.; Defenouillère Q, Namane A, Mouaikel J, Jacquier A, Fromont-Racine M. The ribosome-bound quality control complex remains associated to aberrant peptides during their proteasomal targeting and interacts with Tom1 to limit protein aggregation. Mol Biol Cell. 2017 May 01;28(9):1165–76. PMID: 28298488; PMCID: PMC5415013.; Sitron CS, Park JH, Brandman O. Asc1, Hel2, and Slh1 couple translation arrest to nascent chain degradation. RNA. 2017 May;23(5):798–810. PMID: 28223409; PMCID: PMC5393187.; Juszkiewicz S, Hegde RS. Initiation of Quality Control during Poly(A) Translation Requires Site-Specific Ribosome Ubiquitination. Molecular Cell. 2017 Feb;65(4):743–750.e4. doi: 10.1016/j.molcel.2016.11.039.; Sundaramoorthy E, Leonard M, Mak R, Liao J, Fulzele A, Bennett EJ. ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Quality Control Function by Mediating Regulatory 40S Ribosomal Ubiquitylation. Molecular Cell. 2017 Feb;65(4):751–760.e4. doi: 10.1016/j.molcel.2016.12.026.; Yonashiro R, Tahara EB, Bengtson MH, Khokhrina M, Lorenz H, Chen KC, Kigoshi-Tansho Y, Savas JN, Yates JR, Kay SA, Craig EA, Mogk A, Bukau B, Joazeiro CA. The Rqc2/Tae2 subunit of the ribosome-associated quality control (RQC) complex marks ribosome-stalled nascent polypeptide chains for aggregation. Elife. 2016 Mar 04;5():e11794. PMID: 26943317; PMCID: PMC4805532.; Shao S, Brown A, Santhanam B, Hegde R. Structure and Assembly Pathway of the Ribosome Quality Control Complex. Molecular Cell. 2015 Feb;57(3):433–44. doi: 10.1016/j.molcel.2014.12.015.; Shen PS, Park J, Qin Y, Li X, Parsawar K, Larson MH, Cox J, Cheng Y, Lambowitz AM, Weissman JS, Brandman O, Frost A. Protein synthesis. Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains. Science. 2015 Jan 02;347(6217):75–8. PMID: 25554787; PMCID: PMC4451101.; Lyumkis D, Oliveira dos Passos D, Tahara EB, Webb K, Bennett EJ, Vinterbo S, Potter CS, Carragher B, Joazeiro CAP. Structural basis for translational surveillance by the large ribosomal subunit-associated protein quality control complex. Proc. Natl. Acad. Sci. U.S.A. 2014 Oct 27;111(45):15981–6. doi: 10.1073/pnas.1413882111.; Shao S, Hegde R. Reconstitution of a Minimal Ribosome-Associated Ubiquitination Pathway with Purified Factors. Molecular Cell. 2014 Sep;55(6):880–90. doi: 10.1016/j.molcel.2014.07.006.; Guydosh NR, Green R. Dom34 rescues ribosomes in 3' untranslated regions. Cell. 2014 Feb 27;156(5):950–62. PMID: 24581494; PMCID: PMC4022138.; Saito S, Hosoda N, Hoshino S. The Hbs1-Dom34 Protein Complex Functions in Non-stop mRNA Decay in Mammalian Cells. Journal of Biological Chemistry. 2013 Jun;288(24):17832–43. doi: 10.1074/jbc.m112.448977.; Shao S, von der Malsburg K, Hegde R. Listerin-Dependent Nascent Protein Ubiquitination Relies on Ribosome Subunit Dissociation. Molecular Cell. 2013 Jun;50(5):637–48. doi: 10.1016/j.molcel.2013.04.015.; Defenouillère Q, Yao Y, Mouaikel J, Namane A, Galopier A, Decourty L, Doyen A, Malabat C, Saveanu C, Jacquier A, Fromont-Racine M. Cdc48-associated complex bound to 60S particles is required for the clearance of aberrant translation products. Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5046–51. PMID: 23479637; PMCID: PMC3612664.; Verma R, Oania RS, Kolawa NJ, Deshaies RJ. Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome. Elife. 2013 Jan 22;2():e00308. 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PMID: 22503425.; Becker T, Franckenberg S, Wickles S, Shoemaker CJ, Anger AM, Armache JP, Sieber H, Ungewickell C, Berninghausen O, Daberkow I, Karcher A, Thomm M, Hopfner KP, Green R, Beckmann R. Structural basis of highly conserved ribosome recycling in eukaryotes and archaea. Nature. 2012 Feb 22;482(7386):501–6. PMID: 22358840; PMCID: PMC6878762.; Pisareva VP, Skabkin MA, Hellen CU, Pestova TV, Pisarev AV. Dissociation by Pelota, Hbs1 and ABCE1 of mammalian vacant 80S ribosomes and stalled elongation complexes. EMBO J. 2011 May 04;30(9):1804–17. PMID: 21448132; PMCID: PMC3101999.; Shoemaker CJ, Eyler DE, Green R. Dom34:Hbs1 promotes subunit dissociation and peptidyl-tRNA drop-off to initiate no-go decay. Science. 2010 Oct 15;330(6002):369–72. PMID: 20947765; PMCID: PMC4022135.; Bengtson MH, Joazeiro CA. Role of a ribosome-associated E3 ubiquitin ligase in protein quality control. Nature. 2010 Sep 23;467(7314):470–3. 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Metabolites

ATP(4-)

Formula: C10H12N5O13P3 (502.9644492)

CAS ID:

GTP(4-)

Formula: C10H12N5O14P3 (518.9593642)

CAS ID: 86527-72-2

ADP(3-)

Formula: C10H12N5O10P2 (424.0059412)

CAS ID:



Enzyme

EC Number name full name note
3.6.5.-
2.3.2.23 E2 ubiquitin-conjugating enzyme S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine:[E2 ubiquitin-conjugating enzyme] ubiquitinyl transferase
2.3.2.24 (E3-independent) E2 ubiquitin-conjugating enzyme S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine:L-lysine ubiquitinyl transferase ([E3 ubiquitin transferase]-independent)
4.2.99.18 DNA-(apurinic or apyrimidinic site) lyase DNA-(apurinic or apyrimidinic site) 5'-phosphomonoester-lyase
5.6.2.4 DNA 3'-5' helicase DNA 3'-5' helicase (ATP-hydrolysing)


Proteins

Protein ID name full name