Reactome | Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide

Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide

Stable Identifier

R-HSA-9954709

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide

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After the 80S ribosome is split into a 40S subunit and a 60S subunit that contains the peptidyl-tRNA at the P site, NEMF (the human homolog of yeast RQC2) binds the exposed peptidyl-tRNA of the isolated 60S ribosomal subunit produced by either the RQT complex or ABCE1 and transfers alanine residues from aminoacyl tRNAs to the C-terminus of the nascent peptide, a process termed Carboxy-terminal Alanine and Threonine tailing (CAT-tailing) after the alanine and threonine tails observed in yeast (Udagawa et al. 2021, Thrun et al. 2021, inferred from the yeast homolog RQC2 in Shen et al. 2015, Kostova et al. 2017, Osuna et al. 2017). Structures of CAT-tailing intermediates in yeast indicate that RQC2 positions an aminoacyl-tRNA in the A site of the 60S subunit and eIF5A enables peptidyl transfer (Shen et al. 2015, Tesina et al. 2023).
The alanine C-terminal tails are believed to push the nascent peptide through the exit tunnel of the 60S ribosomal subunit to expose lysine residues for K48 ubiquitination by Listerin (LTN1), however alanine tails can cause aggregation of nascent peptides (Udagawa et al. 2021, and inferred from yeast homologs in Yonashiro et al. 2016). The alanine tails can also act as degrons by binding the CRL2-KHDC10 ubiquitin E3 ligase complex (Thrun et al. 2021, Patil et al. 2023) or the RCHY1 (PIRH2) ubiquitin E3 ligase (Thrun et al. 2021, Patil et al. 2023, Wang et al. 2023) CRL2-KHDC10 and RCHY1 ubiquitinate the nascent peptide using K48 polyubiquitin linkages, targeting the nascent peptide for destruction by the 26S proteasome.
Listerin (LTN1, also called RKR1 in yeast), a ubiquitin E3 ligase, is also capable of K48 ubiquitinating the nascent peptide after NEMF recruits LTN1 to the 60S ribosomal subunit (Shao et al. 2015). The N-terminal region of LTN1 contacts the 60S ribosomal subunit and NEMF while the C-terminal region of LTN1 binds the 60S ribosomal subunit near the exit tunnel (Shao et al. 2015, inferred from yeast homologs in Lyumkis et al. 2014). TCF25 (the homolog of RQC1 in yeast) interacts with LTN1 (inferred from yeast homologs in Defenouillère et al. 2013).
LTN1 ubiquitinates exposed lysine residues on the nascent peptide after the residues have emerged from the exit tunnel of the 60S ribosomal subunit (Osuna et al. 2017, Kuroha et al. 2018, Abaeva et al. 2025, inferred from yeast homologs in Bengtson and Joazeiro 2010, Shao et al. 2013, Shao and Hegde 2014, reviewed in Mishra et al. 2021). TCF25, the human homolog of RQC1 in yeast, interacts with the RING domain of LTN1 to orient the ubiquitin substrate molecules to produce lysine-48 (K48) linkages in the polyubiquitin product (Kuroha et al. 2018, Abaeva et al. 2025).
A hexamer of VCP subunits plus a heterodimer of UFDL1 (UFD1) and NPLOC4 bind polyubiquitin that contains lysine-48 linkages (K48polyUb) and is conjugated to the nascent peptide emerging from the exit tunnel of the 60S ribosomal subunit (Tsuchiya et al. 2017, Sato et al. 2019, Williams et al. 2023, and inferred from CDC48, the yeast orthologue of VCP, in Brandman et al. 2012, Defenouillère et al. 2013, Verma et al. 2013). In yeast, the Npl4:Ufd1 heterodimer (homolog of NPLOC4:UFD1L) acts as an adapter that binds K48-linked polyubiquitin and inserts it into the pore of the VCP hexamer (inferred from rat p97 and Ufd1:Npl4 in Meyer et al. 2000, reviewed in Meyer and van den Boom 2023).
ANKZF1, which interacts with VCP, cleaves the C-terminal 3 nucleotides, CCA, of the tRNA in the peptidyl-tRNA bound to the 60S ribosomal subunit, yielding a free tRNA and the nascent peptide covalently bound to the CCA sequence (Verma et al. 2018, Yip et al. 2019, and inferred from the yeast homolog, VMS1, in Verma et al. 2018, Yip et al. 2019). In yeast, Arb1 (mammalian ABCF2) occupies the E-site of the collided ribosome, extending a domain towards the peptidyl-tRNA that may help position it for release by Vms1/ANKZF1 (Su et al. 2019).
The VCP hexamer then extracts the ubiquitinated nascent peptide from the 60S ribosomal subunit. Six subunits of VCP surround the substrate protein, which is located in the central pore of the hexamer. Hydrolysis of ATP by a subunit causes it to disengage from the hexamer. Release of ADP and binding of ATP causes the subunit to rebind the hexamer more proximally to the 60S ribosomal subunit (reviewed in Meyer and van den Boom 2023). The result is a ratcheting effect that withdraws the nascent peptide from the 60S subunit. The extracted nascent peptide remains bound to the ribosome-associated quality control complex (RQC complex, LTN1:NEMF:TCF25:VCP hexamer) which dissociates from the 60S ribosomal subunit and escorts the nascent peptide to the proteasome (inferred from yeast homologs in Defenouillère et al. 2017). The region of the nascent peptide that is unfolded by the VCP hexamer is able to enter the proteasome, resulting in degradation of the nascent peptide (inferred from the yeast homolog CDC48 in Olszewski et al. 2019). After removal of the ubiquitinated nascent peptide and tRNA, and mRNA, the 60S subunit is able to be re-used in translation.

Literature References

PubMed ID	Title	Journal	Year
37676773	Mechanism and evolutionary origins of alanine-tail C-degron recognition by E3 ligases Pirh2 and CRL2-KLHDC10 Patil, PR, Burroughs, AM, Misra, M, Cerullo, F, Costas-Insua, C, Hung, HC, Dikic, I, Aravind, L, Joazeiro, CAP	Cell Rep	2023
26943317	The Rqc2/Tae2 subunit of the ribosome-associated quality control (RQC) complex marks ribosome-stalled nascent polypeptide chains for aggregation 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	Elife	2016
37120596	Recognition of an Ala-rich C-degron by the E3 ligase Pirh2 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	Nat Commun	2023
28718767	In vitro analysis of RQC activities provides insights into the mechanism and function of CAT tailing Osuna, BA, Howard, CJ, Kc, S, Frost, A, Weinberg, DE	Elife	2017
30675527	The Cdc48 unfoldase prepares well-folded protein substrates for degradation by the 26S proteasome Olszewski, MM, Williams, C, Dong, KC, Martin, A	Commun Biol	2019
40169231	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 Abaeva, IS, Bulakhov, AG, Hellen, CUT, Pestova, TV	Genes Dev	2025
33406423	Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Morphogenesis and Cell Survival Udagawa, T, Seki, M, Okuyama, T, Adachi, S, Natsume, T, Noguchi, T, Matsuzawa, A, Inada, T	Cell Rep	2021
31836717	Structural insights into ubiquitin recognition and Ufd1 interaction of Npl4 Sato, Y, Tsuchiya, H, Yamagata, A, Okatsu, K, Tanaka, K, Saeki, Y, Fukai, S	Nat Commun	2019
31189955	Structure and function of Vms1 and Arb1 in RQC and mitochondrial proteome homeostasis Su, T, Izawa, T, Thoms, M, Yamashita, Y, Cheng, J, Berninghausen, O, Hartl, FU, Inada, T, Neupert, W, Beckmann, R	Nature	2019
28751611	CAT-tailing as a fail-safe mechanism for efficient degradation of stalled nascent polypeptides Kostova, KK, Hickey, KL, Osuna, BA, Hussmann, JA, Frost, A, Weinberg, DE, Weissman, JS	Science	2017
23358411	Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome Verma, R, Oania, RS, Kolawa, NJ, Deshaies, RJ	Elife	2013
28298488	The ribosome-bound quality control complex remains associated to aberrant peptides during their proteasomal targeting and interacts with Tom1 to limit protein aggregation Defenouillère, Q, Namane, A, Mouaikel, J, Jacquier, A, Fromont-Racine, M	Mol Biol Cell	2017
30244831	Release of Ubiquitinated and Non-ubiquitinated Nascent Chains from Stalled Mammalian Ribosomal Complexes by ANKZF1 and Ptrh1 Kuroha, K, Zinoviev, A, Hellen, CUT, Pestova, TV	Mol Cell	2018
31011209	Mechanism for recycling tRNAs on stalled ribosomes Yip, MCJ, Keszei, AFA, Feng, Q, Chu, V, McKenna, MJ, Shao, S	Nat Struct Mol Biol	2019
28525741	In Vivo Ubiquitin Linkage-type Analysis Reveals that the Cdc48-Rad23/Dsk2 Axis Contributes to K48-Linked Chain Specificity of the Proteasome Tsuchiya, H, Ohtake, F, Arai, N, Kaiho, A, Yasuda, S, Tanaka, K, Saeki, Y	Mol Cell	2017
23178123	A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress Brandman, O, Stewart-Ornstein, J, Wong, D, Larson, A, Williams, CC, Li, GW, Zhou, S, King, D, Shen, PS, Weibezahn, J, Dunn, JG, Rouskin, S, Inada, T, Frost, A, Weissman, JS	Cell	2012
32011234	Distinct regulatory ribosomal ubiquitylation events are reversible and hierarchically organized Garshott, DM, Sundaramoorthy, E, Leonard, M, Bennett, EJ	Elife	2020
36804914	Molecular basis of eIF5A-dependent CAT tailing in eukaryotic ribosome-associated quality control Tesina, P, Ebine, S, Buschauer, R, Thoms, M, Matsuo, Y, Inada, T, Beckmann, R	Mol Cell	2023
25578875	Structure and assembly pathway of the ribosome quality control complex Shao, S, Brown, A, Santhanam, B, Hegde, RS	Mol Cell	2015
31981475	The G3BP1-Family-USP10 Deubiquitinase Complex Rescues Ubiquitinated 40S Subunits of Ribosomes Stalled in Translation from Lysosomal Degradation Meyer, C, Garzia, A, Morozov, P, Molina, H, Tuschl, T	Mol Cell	2020
36825201	Targeting of client proteins to the VCP/p97/Cdc48 unfolding machine Meyer, H, van den Boom, J	Front Mol Biosci	2023
25132172	Reconstitution of a minimal ribosome-associated ubiquitination pathway with purified factors Shao, S, Hegde, RS	Mol Cell	2014
25349383	Structural basis for translational surveillance by the large ribosomal subunit-associated protein quality control complex Lyumkis, D, Oliveira dos Passos, D, Tahara, EB, Webb, K, Bennett, EJ, Vinterbo, S, Potter, CS, Carragher, B, Joazeiro, CA	Proc Natl Acad Sci U S A	2014
23479637	Cdc48-associated complex bound to 60S particles is required for the clearance of aberrant translation products Defenouillère, Q, Yao, Y, Mouaikel, J, Namane, A, Galopier, A, Decourty, L, Doyen, A, Malabat, C, Saveanu, C, Jacquier, A, Fromont-Racine, M	Proc Natl Acad Sci U S A	2013
34590243	LISTERIN E3 Ubiquitin Ligase and Ribosome-Associated Quality Control (RQC) Mechanism Mishra, R, Bansal, A, Mishra, A	Mol Neurobiol	2021
25554787	Protein synthesis. Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains Shen, PS, Park, J, Qin, Y, Li, X, Parsawar, K, Larson, MH, Cox, J, Cheng, Y, Lambowitz, AM, Weissman, JS, Brandman, O, Frost, A	Science	2015
20835226	Role of a ribosome-associated E3 ubiquitin ligase in protein quality control Bengtson, MH, Joazeiro, CA	Nature	2010
36736315	The Ufd1 cofactor determines the linkage specificity of polyubiquitin chain engagement by the AAA+ ATPase Cdc48 Williams, C, Dong, KC, Arkinson, C, Martin, A	Mol Cell	2023
33909987	Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing 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	Mol Cell	2021