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.
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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).
- 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.