Review Article | Published:

Mechanisms and functions of ribosome-associated protein quality control


The stalling of ribosomes during protein synthesis results in the production of truncated polypeptides that can have deleterious effects on cells and therefore must be eliminated. In eukaryotes, this function is carried out by a dedicated surveillance mechanism known as ribosome-associated protein quality control (RQC). The E3 ubiquitin ligase Ltn1 (listerin in mammals) plays a key part in RQC by targeting the aberrant nascent polypeptides for proteasomal degradation. Consistent with having an important protein quality control function, mutations in listerin cause neurodegeneration in mice. Ltn1/listerin is part of the multisubunit RQC complex, and recent findings have revealed that the Rqc2 subunit of this complex catalyses the formation of carboxy-terminal alanine and threonine tails (CAT tails), which are extensions of nascent chains known to either facilitate substrate ubiquitylation and targeting for degradation or induce protein aggregation. RQC, originally described for quality control on ribosomes translating cytosolic proteins, is now known to also have a role on the surfaces of the endoplasmic reticulum and mitochondria. This Review describes our current knowledge on RQC mechanisms, highlighting key features of Ltn1/listerin action that provide a paradigm for understanding how E3 ligases operate in protein quality control in general, and discusses how defects in this pathway may compromise cellular function and lead to disease.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Pilla, E., Schneider, K. & Bertolotti, A. Coping with protein quality control failure. Annu. Rev. Cell Dev. Biol. 33, 439–465 (2017).

  2. 2.

    Klaips, C. L., Jayaraj, G. G. & Hartl, F. U. Pathways of cellular proteostasis in aging and disease. J. Cell Biol. 217, 51–63 (2018).

  3. 3.

    Hartl, F. U. Protein misfolding diseases. Annu. Rev. Biochem. 86, 21–26 (2017).

  4. 4.

    Joazeiro, C. A. P. Ribosomal stalling during translation: providing substrates for ribosome-associated protein quality control. Annu. Rev. Cell Dev. Biol. 33, 343–368 (2017).

  5. 5.

    Buskirk, A. R. & Green, R. Ribosome pausing, arrest and rescue in bacteria and eukaryotes. Phil. Trans. R. Soc. B 372, 20160183 (2017).

  6. 6.

    Bengtson, M. H. & Joazeiro, C. A. Role of a ribosome-associated E3 ubiquitin ligase in protein quality control. Nature 467, 470–473 (2010). This seminal work identifies Ltn1 as an E3 ligase that marks nascent chains produced by ribosome stalling for degradation while still ribosome associated, defining a previously unknown specialized pathway of protein quality control — RQC.

  7. 7.

    Brandman, O. & Hegde, R. S. Ribosome-associated protein quality control. Nat. Struct. Mol. Biol. 23, 7–15 (2016).

  8. 8.

    Chu, J. et al. A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration. Proc. Nat. Acad. Sci. USA 106, 2097–2103 (2009). This study establishes a first link between listerin–RQC and neurodegeneration.

  9. 9.

    Brandman, O. et al. A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress. Cell 151, 1042–1054 (2012).

  10. 10.

    Defenouillere, Q. et al. Cdc48-associated complex bound to 60S particles is required for the clearance of aberrant translation products. Proc. Nat. Acad. Sci. USA 110, 5046–5051 (2013). This study and that of Brandman et al. (2012) report the results of a powerful combination of genetic and proteomic analyses, uncovering that Ltn1 functions together with cofactors in an RQC complex.

  11. 11.

    Wang, F., Canadeo, L. A. & Huibregtse, J. M. Ubiquitination of newly synthesized proteins at the ribosome. Biochimie 114, 127–133 (2015).

  12. 12.

    Duttler, S., Pechmann, S. & Frydman, J. Principles of cotranslational ubiquitination and quality control at the ribosome. Mol. Cell 50, 379–393 (2013).

  13. 13.

    Shoemaker, C. J., Eyler, D. E. & Green, R. Dom34:Hbs1 promotes subunit dissociation and peptidyl-tRNA drop-off to initiate no-go decay. Science 330, 369–372 (2010).

  14. 14.

    Pisareva, V. P., Skabkin, M. A., Hellen, C. U., Pestova, T. V. & Pisarev, A. V. Dissociation by Pelota, Hbs1 and ABCE1 of mammalian vacant 80S ribosomes and stalled elongation complexes. EMBO J. 30, 1804–1817 (2011).

  15. 15.

    Schuller, A. P. & Green, R. Roadblocks and resolutions in eukaryotic translation. Nat. Rev. Mol. Cell. Biol. 19, 526–541 (2018).

  16. 16.

    Shoemaker, C. J. & Green, R. Translation drives mRNA quality control. Nat. Struct. Mol. Biol. 19, 594–601 (2012).

  17. 17.

    Graille, M. & Seraphin, B. Surveillance pathways rescuing eukaryotic ribosomes lost in translation. Nat. Rev. Mol. Cell. Biol. 13, 727–735 (2012).

  18. 18.

    Arribere, J. A. & Fire, A. Z. Nonsense mRNA suppression via nonstop decay. eLife 7, e33292 (2018).

  19. 19.

    Shao, S., von der Malsburg, K. & Hegde, R. S. Listerin-dependent nascent protein ubiquitination relies on ribosome subunit dissociation. Mol. Cell 50, 637–648 (2013). Further developing studies from Shoemaker et al. (2010) and Pisareva et al. (2011), this work reports biochemical evidence that the dissociation of stalled ribosomal subunits by rescue factors is required upstream of listerin function.

  20. 20.

    Lyumkis, D. et al. Structural basis for translational surveillance by the large ribosomal subunit-associated protein quality control complex. Proc. Nat. Acad. Sci. USA 111, 15981–15986 (2014). This study reports the first cryo-EM structure of the RQC complex, identifying Rqc2 as the subunit that senses obstructed 60S subunits and setting forth novel principles of substrate recognition and selectivity in protein quality control.

  21. 21.

    Shen, P. S. et al. Protein synthesis. Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains. Science 347, 75–78 (2015). This work reports the surprising discovery of CAT tails and offers an underlying mechanism, mediated by Ala-RNA and Thr-tRNA recruitment by Rqc2.

  22. 22.

    Shao, S., Brown, A., Santhanam, B. & Hegde, R. S. Structure and assembly pathway of the ribosome quality control complex. Mol. Cell 57, 433–444 (2015). This work describes the high-resolution cryo-EM structure of the mammalian RQC complex and an elegant biochemical reconstitution of the complex assembly.

  23. 23.

    Verma, R., Oania, R. S., Kolawa, N. J. & Deshaies, R. J. Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome. eLife 2, e00308 (2013).

  24. 24.

    Verma, R. et al. Vms1 and ANKZF1 peptidyl-tRNA hydrolases release nascent chains from stalled ribosomes. Nature 557, 446–451 (2018).

  25. 25.

    Zurita Rendon, O. et al. Vms1p is a release factor for the ribosome-associated quality control complex. Nat. Commun. 9, 2197 (2018). Together with Verma et al. (2018), this study reports that Vms1 acts in releasing the nascent chain from tRNA in an obstructed 60S–peptidyl-tRNA complex.

  26. 26.

    Kostova, K. K. et al. CAT-tailing as a fail-safe mechanism for efficient degradation of stalled nascent polypeptides. Science 357, 414–417 (2017).

  27. 27.

    Osuna, B. A., Howard, C. J., Kc, S., Frost, A. & Weinberg, D. E. In vitro analysis of RQC activities provides insights into the mechanism and function of CAT tailing. eLife 6, e27949 (2017).

  28. 28.

    Yonashiro, R. et al. The Rqc2/Tae2 subunit of the ribosome-associated quality control (RQC) complex marks ribosome-stalled nascent polypeptide chains for aggregation. eLife 5, e11794 (2016).

  29. 29.

    Choe, Y. J. et al. Failure of RQC machinery causes protein aggregation and proteotoxic stress. Nature 531, 191–195 (2016).

  30. 30.

    Defenouillere, Q. et al. Rqc1 and Ltn1 prevent C-terminal alanine-threonine tail (CAT-tail)-induced protein aggregation by efficient recruitment of Cdc48 on stalled 60S subunits. J. Biol. Chem. 291, 12245–12253 (2016). Together with Kostova et al. (2017), Yonashiro et al. (2016) and Choe et al. (2016), this study reports work elucidating consequences of the modification of nascent chains with CAT tails.

  31. 31.

    Ito-Harashima, S., Kuroha, K., Tatematsu, T. & Inada, T. Translation of the poly(A) tail plays crucial roles in nonstop mRNA surveillance via translation repression and protein destabilization by proteasome in yeast. Genes Dev. 21, 519–524 (2007).

  32. 32.

    Wilson, M. A., Meaux, S. & van Hoof, A. A genomic screen in yeast reveals novel aspects of nonstop mRNA metabolism. Genetics 177, 773–784 (2007).

  33. 33.

    Sung, M. K. et al. A conserved quality-control pathway that mediates degradation of unassembled ribosomal proteins. eLife 5, e19105 (2016).

  34. 34.

    Xu, Y., Anderson, D. E. & Ye, Y. The HECT domain ubiquitin ligase HUWE1 targets unassembled soluble proteins for degradation. Cell Discov. 2, 16040 (2016).

  35. 35.

    Khosrow-Khavar, F. et al. The yeast ubr1 ubiquitin ligase participates in a prominent pathway that targets cytosolic thermosensitive mutants for degradation. G3 2, 619–628 (2012).

  36. 36.

    Nillegoda, N. B. et al. Ubr1 and ubr2 function in a quality control pathway for degradation of unfolded cytosolic proteins. Mol. Biol. Cell 21, 2102–2116 (2010).

  37. 37.

    Heck, J. W., Cheung, S. K. & Hampton, R. Y. Cytoplasmic protein quality control degradation mediated by parallel actions of the E3 ubiquitin ligases Ubr1 and San1. Proc. Natl Acad. Sci. USA 107, 1106–1111 (2010).

  38. 38.

    Eisele, F. & Wolf, D. H. Degradation of misfolded protein in the cytoplasm is mediated by the ubiquitin ligase Ubr1. FEBS Lett. 582, 4143–4146 (2008).

  39. 39.

    Wu, X. & Rapoport, T. A. Mechanistic insights into ER-associated protein degradation. Curr. Opin. Cell Biol. 53, 22–28 (2018).

  40. 40.

    Jones, R. D. & Gardner, R. G. Protein quality control in the nucleus. Curr. Opin. Cell Biol. 40, 81–89 (2016).

  41. 41.

    Khmelinskii, A. et al. Protein quality control at the inner nuclear membrane. Nature 516, 410–413 (2014).

  42. 42.

    Foresti, O., Rodriguez-Vaello, V., Funaya, C. & Carvalho, P. Quality control of inner nuclear membrane proteins by the Asi complex. Science 346, 751–755 (2014).

  43. 43.

    Taipale, M. et al. A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. Cell 158, 434–448 (2014).

  44. 44.

    Murata, S., Chiba, T. & Tanaka, K. CHIP: a quality-control E3 ligase collaborating with molecular chaperones. Int. J. Biochem. Cell Biol. 35, 572–578 (2003).

  45. 45.

    Kevei, E., Pokrzywa, W. & Hoppe, T. Repair or destruction-an intimate liaison between ubiquitin ligases and molecular chaperones in proteostasis. FEBS Lett. 591, 2616–2635 (2017).

  46. 46.

    Rosenbaum, J. C. et al. Disorder targets misorder in nuclear quality control degradation: a disordered ubiquitin ligase directly recognizes its misfolded substrates. Mol. Cell 41, 93–106 (2011).

  47. 47.

    Lyumkis, D. et al. Single-particle EM reveals extensive conformational variability of the Ltn1 E3 ligase. Proc. Natl Acad. Sci. USA 110, 1702–1707 (2013).

  48. 48.

    Doamekpor, S. K. et al. Structure and function of the yeast listerin (Ltn1) conserved N-terminal domain in binding to stalled 60S ribosomal subunits. Proc. Natl Acad. Sci. USA 113, E4151–E4160 (2016).

  49. 49.

    McGinty, R. K., Henrici, R. C. & Tan, S. Crystal structure of the PRC1 ubiquitylation module bound to the nucleosome. Nature 514, 591–596 (2014).

  50. 50.

    Brown, N. G. et al. RING E3 mechanism for ubiquitin ligation to a disordered substrate visualized for human anaphase-promoting complex. Proc. Natl Acad. Sci. USA 112, 5272–5279 (2015).

  51. 51.

    Deshaies, R. J. & Joazeiro, C. A. RING domain E3 ubiquitin ligases. Annu. Rev. Biochem. 78, 399–434 (2009).

  52. 52.

    Breitschopf, K., Bengal, E., Ziv, T., Admon, A. & Ciechanover, A. A novel site for ubiquitination: the N-terminal residue, and not internal lysines of MyoD, is essential for conjugation and degradation of the protein. EMBO J. 17, 5964–5973 (1998).

  53. 53.

    McDowell, G. S. & Philpott, A. Non-canonical ubiquitylation: mechanisms and consequences. Int. J. Biochem. Cell Biol. 45, 1833–1842 (2013).

  54. 54.

    Kravtsova-Ivantsiv, Y. & Ciechanover, A. Non-canonical ubiquitin-based signals for proteasomal degradation. J. Cell Sci. 125, 539–548 (2012).

  55. 55.

    Pao, K. C. et al. Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity. Nature 556, 381–385 (2018).

  56. 56.

    Weber, A. et al. Sequential poly-ubiquitylation by specialized conjugating enzymes expands the versatility of a quality control ubiquitin ligase. Mol. Cell 63, 827–839 (2016).

  57. 57.

    Boban, M., Ljungdahl, P. O. & Foisner, R. Atypical ubiquitylation in yeast targets lysine-less Asi2 for proteasomal degradation. J. Biol. Chem. 290, 2489–2495 (2015).

  58. 58.

    Ishikura, S., Weissman, A. M. & Bonifacino, J. S. Serine residues in the cytosolic tail of the T cell antigen receptor alpha-chain mediate ubiquitination and endoplasmic reticulum-associated degradation of the unassembled protein. J. Biol. Chem. 285, 23916–23924 (2010).

  59. 59.

    Shimizu, Y., Okuda-Shimizu, Y. & Hendershot, L. M. Ubiquitylation of an ERAD substrate occurs on multiple types of amino acids. Mol. Cell 40, 917–926 (2010).

  60. 60.

    Skaar, J. R., Pagan, J. K. & Pagano, M. Mechanisms and function of substrate recruitment by F-box proteins. Nat. Rev. Mol. Cell. Biol. 14, 369–381 (2013).

  61. 61.

    Duda, D. M. et al. Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation. Cell 134, 995–1006 (2008).

  62. 62.

    Fischer, E. S. et al. The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation. Cell 147, 1024–1039 (2011).

  63. 63.

    Ghaemmaghami, S. et al. Global analysis of protein expression in yeast. Nature 425, 737–741 (2003).

  64. 64.

    Shao, S. & Hegde, R. S. Reconstitution of a minimal ribosome-associated ubiquitination pathway with purified factors. Mol. Cell 55, 880–890 (2014).

  65. 65.

    Lu, J. & Deutsch, C. Electrostatics in the ribosomal tunnel modulate chain elongation rates. J. Mol. Biol. 384, 73–86 (2008).

  66. 66.

    Izawa, T., Park, S. H., Zhao, L., Hartl, F. U. & Neupert, W. Cytosolic protein Vms1 links ribosome quality control to mitochondrial and cellular homeostasis. Cell 171, 890–903 (2017). This is an elegant analysis that first reports consequences of RQC dysfunction regarding cytosolic ribosomes stalled while translating mitochondrial proteins (mito–RQC).

  67. 67.

    Sontag, E. M., Samant, R. S. & Frydman, J. Mechanisms and functions of spatial protein quality control. Annu. Rev. Biochem. 86, 97–122 (2017).

  68. 68.

    Miller, S. B., Mogk, A. & Bukau, B. Spatially organized aggregation of misfolded proteins as cellular stress defense strategy. J. Mol. Biol. 427, 1564–1574 (2015).

  69. 69.

    Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell. Biol. 19, 349–364 (2018).

  70. 70.

    Spokoini, R. et al. Confinement to organelle-associated inclusion structures mediates asymmetric inheritance of aggregated protein in budding yeast. Cell Rep. 2, 738–747 (2012).

  71. 71.

    Gomez-Pastor, R., Burchfiel, E. T. & Thiele, D. J. Regulation of heat shock transcription factors and their roles in physiology and disease. Nat. Rev. Mol. Cell. Biol. 19, 4–19 (2018).

  72. 72.

    Anckar, J. & Sistonen, L. Regulation of HSF1 function in the heat stress response: implications in aging and disease. Annu. Rev. Biochem. 80, 1089–1115 (2011).

  73. 73.

    Nissen, P., Hansen, J., Ban, N., Moore, P. B. & Steitz, T. A. The structural basis of ribosome activity in peptide bond synthesis. Science 289, 920–930 (2000).

  74. 74.

    Kuroha, K., Zinoviev, A., Hellen, C. U. T. & Pestova, T. V. Release of ubiquitinated and non-ubiquitinated nascent chains from stalled mammalian ribosomal complexes by ANKZF1 and Ptrh1. Mol. Cell 72, 286–302 (2018).

  75. 75.

    Defenouillere, 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 28, 1165–1176 (2017).

  76. 76.

    Meyer, H., Bug, M. & Bremer, S. Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat. Cell Biol. 14, 117–123 (2012).

  77. 77.

    Shcherbik, N., Chernova, T. A., Chernoff, Y. O. & Pestov, D. G. Distinct types of translation termination generate substrates for ribosome-associated quality control. Nucleic Acid Res. 44, 6840–6852 (2016).

  78. 78.

    Tsuchiya, H. et al. In vivo ubiquitin linkage-type analysis reveals that the Cdc48-Rad23/Dsk2 axis contributes to K48-linked chain specificity of the proteasome. Mol. Cell 66, 488–502 (2017).

  79. 79.

    Simms, C. L. & Zaher, H. S. Ribosome collision is critical for quality control during no-go decay. Mol. Cell 68, 361–373 (2017).

  80. 80.

    Wesolowska, M. T., Richter-Dennerlein, R., Lightowlers, R. N. & Chrzanowska-Lightowlers, Z. M. Overcoming stalled translation in human mitochondria. Front. Microbiol. 5, 374 (2014).

  81. 81.

    Izawa, T. et al. Roles of dom34:hbs1 in nonstop protein clearance from translocators for normal organelle protein influx. Cell Rep. 2, 447–453 (2012).

  82. 82.

    Arakawa, S. et al. Quality control of nonstop membrane proteins at the ER membrane and in the cytosol. Sci. Rep. 6, 30795 (2016).

  83. 83.

    Crowder, J. J. et al. Rkr1/Ltn1 ubiquitin ligase-mediated degradation of translationally stalled endoplasmic reticulum proteins. J. Biol. Chem. 290, 18454–18466 (2015).

  84. 84.

    von der Malsburg, K., Shao, S. & Hegde, R. S. The ribosome quality control pathway can access nascent polypeptides stalled at the Sec61 translocon. Mol. Biol. Cell 26, 2168–2180 (2015).

  85. 85.

    Moore, S. D. & Sauer, R. T. The tmRNA system for translational surveillance and ribosome rescue. Annu. Rev. Biochem. 76, 101–124 (2007).

  86. 86.

    Lang, W. H., Calloni, G. & Vabulas, R. M. Polylysine is a proteostasis network-engaging structural determinant. J. Proteome Res. 17, 1967–1977 (2018).

  87. 87.

    Saarikangas, J. & Barral, Y. Protein aggregation as a mechanism of adaptive cellular responses. Curr. Genet. 62, 711–724 (2016).

  88. 88.

    Wang, Y., Meriin, A. B., Costello, C. E. & Sherman, M. Y. Characterization of proteins associated with polyglutamine aggregates: a novel approach towards isolation of aggregates from protein conformation disorders. Prion 1, 128–135 (2007).

  89. 89.

    Rousseau, E. et al. Targeting expression of expanded polyglutamine proteins to the endoplasmic reticulum or mitochondria prevents their aggregation. Proc. Natl Acad. Sci. USA 101, 9648–9653 (2004).

  90. 90.

    Schneider, K. & Bertolotti, A. Surviving protein quality control catastrophes—from cells to organisms. J. Cell Sci. 128, 3861–3869 (2015).

  91. 91.

    Ishimura, R. et al. RNA function. Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration. Science 345, 455–459 (2014).

  92. 92.

    Taylor, J. P., Brown, R. H. Jr & Cleveland, D. W. Decoding ALS: from genes to mechanism. Nature 539, 197–206 (2016).

  93. 93.

    Dawson, T. M. & Dawson, V. L. Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302, 819–822 (2003).

  94. 94.

    Bauer, M. F. & Neupert, W. Import of proteins into mitochondria: a novel pathomechanism for progressive neurodegeneration. J. Inherit. Metab. Dis. 24, 166–180 (2001).

  95. 95.

    Sarkar, A. et al. Preribosomes escaping from the nucleus are caught during translation by cytoplasmic quality control. Nat. Struct. Mol. Biol. 24, 1107–1115 (2017).

  96. 96.

    Juszkiewicz, S. & Hegde, R. S. Initiation of quality control during poly(A) translation requires site-specific ribosome ubiquitination. Mol. Cell 65, 743–750 (2017).

  97. 97.

    Arthur, L. et al. Translational control by lysine-encoding A-rich sequences. Sci. Adv. 1, e1500154 (2015).

  98. 98.

    Ito, K. & Chiba, S. Arrest peptides: cis-acting modulators of translation. Annu. Rev. Biochem. 82, 171–202 (2013).

  99. 99.

    Hilal, T. et al. Structural insights into ribosomal rescue by Dom34 and Hbs1 at near-atomic resolution. Nat. Commun. 7, 13521 (2016).

  100. 100.

    Matsuo, Y. et al. Ubiquitination of stalled ribosome triggers ribosome-associated quality control. Nat. Commun. 8, 159 (2017).

  101. 101.

    Sundaramoorthy, E. et al. ZNF598 and RACK1 regulate mammalian ribosome-associated quality control function by mediating regulatory 40S ribosomal ubiquitylation. Mol. Cell 65, 751–760 (2017).

  102. 102.

    Sitron, C. S., Park, J. H. & Brandman, O. Asc1, Hel2, and Slh1 couple translation arrest to nascent chain degradation. RNA 23, 798–810 (2017).

  103. 103.

    Garzia, A. et al. The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs. Nat. Commun. 8, 16056 (2017).

  104. 104.

    Simms, C. L., Thomas, E. N. & Zaher, H. S. Ribosome-based quality control of mRNA and nascent peptides. RNA 8, e1366 (2017).

  105. 105.

    Li, W. et al. Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling. PLOS ONE 3, e1487 (2008).

  106. 106.

    Wenzel, D. M., Lissounov, A., Brzovic, P. S. & Klevit, R. E. UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature 474, 105–108 (2011).

  107. 107.

    Buetow, L. & Huang, D. T. Structural insights into the catalysis and regulation of E3 ubiquitin ligases. Nat. Rev. Mol. Cell. Biol. 17, 626–642 (2016).

  108. 108.

    Kao, S. H., Wu, H. T. & Wu, K. J. Ubiquitination by HUWE1 in tumorigenesis and beyond. J. Biomed. Sci. 25, 67 (2018).

  109. 109.

    Varshavsky, A. The ubiquitin system, autophagy, and regulated protein degradation. Annu. Rev. Biochem. 86, 123–128 (2017).

  110. 110.

    Joazeiro, C. A. et al. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science 286, 309–312 (1999).

  111. 111.

    Zuzow, N. et al. Mapping the mammalian ribosome quality control complex interactome using proximity labeling approaches. Mol. Biol. Cell 29, 1258–1269 (2018).

  112. 112.

    Ossareh-Nazari, B. et al. Ubiquitylation by the Ltn1 E3 ligase protects 60S ribosomes from starvation-induced selective autophagy. J. Cell Biol. 204, 909–917 (2014).

  113. 113.

    Defenouillere, Q. & Fromont-Racine, M. The ribosome-bound quality control complex: from aberrant peptide clearance to proteostasis maintenance. Curr. Genet. 63, 997–1005 (2017).

  114. 114.

    Shoemaker, C. J. & Green, R. Kinetic analysis reveals the ordered coupling of translation termination and ribosome recycling in yeast. Proc. Natl Acad. Sci. USA 108, E1392–E1398 (2011).

Download references


The author thanks members of the Joazeiro laboratory for comments on the manuscript and is also grateful to T. Hilal, C. Spahn, S. Tan and members of the Joazeiro laboratory for preparing figures, especially to H. Paternoga for Figure 2. Work in the Joazeiro laboratory is supported by a grant from the Deutsche Forschungsgemeinschaft (SFB1036; ZMBH) and by R01 Grants NS075719 and NS102414 from the National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health (Scripps).

Author information

Competing interests

The author declares no competing interests.

Correspondence to Claudio A. P. Joazeiro.


RING domain

A globular protein domain that characterizes the vast majority of E3 ligases and functions by recruiting E2 conjugases and sometimes by additionally binding the E2-conjugated ubiquitin moiety to prime it for transfer.

Endoplasmic reticulum-associated degradation

(ERAD). The process by which aberrant proteins in the lumen or membrane of the endoplasmic reticulum (ER) are ubiquitylated by ER-membrane-resident E3 ligases and retrotranslocated for degradation in the cytosol.

N-end rule pathway

A ubiquitylation pathway that targets proteins for degradation as a function of their amino-terminal residue.


Protein complexes on organellar surfaces that mediate import of proteins made in the cytosol (this term being most commonly utilized in endoplasmic reticulum studies).

Cullin-dependent E3 ligase

An E3 ligase complex consisting of a RING domain subunit (Rbx1 or Rbx2), a cullin subunit and adaptor proteins that link the RING–cullin subunit core to substrates.


A cellular inclusion containing misfolded proteins and formed in a regulated manner, typically increased under stress.

Ribonuclease H

A family of endonuclease enzymes that cleave RNA phosphodiester bonds in an RNA–DNA duplex in a sequence-unspecific manner.


A hybrid transfer-messenger RNA (tmRNA) molecule that is a central component of the bacterial pathway of ribosomal rescue and protein quality control elicited in response to translational stalling.


The selective autophagy of 60S ribosomal subunits in response to nutrient starvation requiring the deubiquitylating enzyme Ubp3 in yeast.

Hypomorphic mutation

A recessive mutation that causes partial loss of gene function owing to reduced activity or expression.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1: The eukaryotic ribosome-associated quality control pathway.
Fig. 2: The function of Ltn1/listerin in protein surveillance.
Fig. 3: CAT-tail synthesis and functions.
Fig. 4: RQC on the endoplasmic reticulum and mitochondrial membranes.