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      Mechanisms and functions of ribosome-associated protein quality control

      Nature Reviews Molecular Cell Biology
      Springer Nature

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          Abstract

          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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          Most cited references63

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          The structural basis of ribosome activity in peptide bond synthesis.

          Using the atomic structures of the large ribosomal subunit from Haloarcula marismortui and its complexes with two substrate analogs, we establish that the ribosome is a ribozyme and address the catalytic properties of its all-RNA active site. Both substrate analogs are contacted exclusively by conserved ribosomal RNA (rRNA) residues from domain V of 23S rRNA; there are no protein side-chain atoms closer than about 18 angstroms to the peptide bond being synthesized. The mechanism of peptide bond synthesis appears to resemble the reverse of the acylation step in serine proteases, with the base of A2486 (A2451 in Escherichia coli) playing the same general base role as histidine-57 in chymotrypsin. The unusual pK(a) (where K(a) is the acid dissociation constant) required for A2486 to perform this function may derive in part from its hydrogen bonding to G2482 (G2447 in E. coli), which also interacts with a buried phosphate that could stabilize unusual tautomers of these two bases. The polypeptide exit tunnel is largely formed by RNA but has significant contributions from proteins L4, L22, and L39e, and its exit is encircled by proteins L19, L22, L23, L24, L29, and L31e.
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            Molecular pathways of neurodegeneration in Parkinson's disease.

            Parkinson's disease (PD) is a complex disorder with many different causes, yet they may intersect in common pathways, raising the possibility that neuroprotective agents may have broad applicability in the treatment of PD. Current evidence suggests that mitochondrial complex I inhibition may be the central cause of sporadic PD and that derangements in complex I cause alpha-synuclein aggregation, which contributes to the demise of dopamine neurons. Accumulation and aggregation of alpha-synuclein may further contribute to the death of dopamine neurons through impairments in protein handling and detoxification. Dysfunction of parkin (a ubiquitin E3 ligase) and DJ-1 could contribute to these deficits. Strategies aimed at restoring complex I activity, reducing oxidative stress and alpha-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.
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              Genome-Wide and Functional Annotation of Human E3 Ubiquitin Ligases Identifies MULAN, a Mitochondrial E3 that Regulates the Organelle's Dynamics and Signaling

              Specificity of protein ubiquitylation is conferred by E3 ubiquitin (Ub) ligases. We have annotated ∼617 putative E3s and substrate-recognition subunits of E3 complexes encoded in the human genome. The limited knowledge of the function of members of the large E3 superfamily prompted us to generate genome-wide E3 cDNA and RNAi expression libraries designed for functional screening. An imaging-based screen using these libraries to identify E3s that regulate mitochondrial dynamics uncovered MULAN/FLJ12875, a RING finger protein whose ectopic expression and knockdown both interfered with mitochondrial trafficking and morphology. We found that MULAN is a mitochondrial protein – two transmembrane domains mediate its localization to the organelle's outer membrane. MULAN is oriented such that its E3-active, C-terminal RING finger is exposed to the cytosol, where it has access to other components of the Ub system. Both an intact RING finger and the correct subcellular localization were required for regulation of mitochondrial dynamics, suggesting that MULAN's downstream effectors are proteins that are either integral to, or associated with, mitochondria and that become modified with Ub. Interestingly, MULAN had previously been identified as an activator of NF-κB, thus providing a link between mitochondrial dynamics and mitochondria-to-nucleus signaling. These findings suggest the existence of a new, Ub-mediated mechanism responsible for integration of mitochondria into the cellular environment.
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                Author and article information

                Journal
                Nature Reviews Molecular Cell Biology
                Nat Rev Mol Cell Biol
                Springer Nature
                1471-0072
                1471-0080
                April 2 2019
                Article
                10.1038/s41580-019-0118-2
                7138134
                30940912
                ea413442-ce75-4003-b357-a7bc004bbaab
                © 2019

                http://www.springer.com/tdm

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