scholarly journals The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation

2019 ◽  
Author(s):  
Andrea Hildebrandt ◽  
Mirko Brüggemann ◽  
Susan Boerner ◽  
Cornelia Rücklé ◽  
Jan Bernhard Heidelberger ◽  
...  
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Rna Binding ◽  
Mrna Level ◽  
Ring Finger ◽  
Common Source ◽  
Control Mechanisms ◽  
Functional Protein ◽  
Ribosome Stalling ◽  
Translational Regulators

AbstractCells have evolved quality control mechanisms to ensure protein homeostasis by detecting and degrading aberrant mRNAs and proteins. A common source of aberrant mRNAs is premature polyadenylation, which can result in non-functional protein products. Translating ribosomes that encounter poly(A) sequences are terminally stalled, followed by ribosome recycling and decay of the truncated nascent polypeptide via the ribosome-associated quality control (RQC). Here, we demonstrate that the conserved RNA-binding E3 ubiquitin ligase Makorin Ring Finger Protein 1 (MKRN1) promotes ribosome stalling at poly(A) sequences during RQC. We show that MKRN1 interacts with the cytoplasmic poly(A)-binding protein (PABP) and is positioned upstream of poly(A) tails in mRNAs. Ubiquitin remnant profiling uncovers PABP and ribosomal protein RPS10, as well as additional translational regulators as main ubiquitylation substrates of MKRN1. We propose that MKRN1 serves as a first line of poly(A) recognition at the mRNA level to prevent production of erroneous proteins, thus maintaining proteome integrity.

scholarly journals The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Andrea Hildebrandt ◽  
Mirko Brüggemann ◽  
Cornelia Rücklé ◽  
Susan Boerner ◽  
Jan B. Heidelberger ◽  
...  
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Rna Binding ◽  
Ring Finger ◽  
Common Source ◽  
Control Mechanisms ◽  
Dependent Manner ◽  
Functional Protein ◽  
Ribosome Stalling

Abstract Background Cells have evolved quality control mechanisms to ensure protein homeostasis by detecting and degrading aberrant mRNAs and proteins. A common source of aberrant mRNAs is premature polyadenylation, which can result in non-functional protein products. Translating ribosomes that encounter poly(A) sequences are terminally stalled, followed by ribosome recycling and decay of the truncated nascent polypeptide via ribosome-associated quality control. Results Here, we demonstrate that the conserved RNA-binding E3 ubiquitin ligase Makorin Ring Finger Protein 1 (MKRN1) promotes ribosome stalling at poly(A) sequences during ribosome-associated quality control. We show that MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) and associates with polysomes. MKRN1 is positioned upstream of poly(A) tails in mRNAs in a PABPC1-dependent manner. Ubiquitin remnant profiling and in vitro ubiquitylation assays uncover PABPC1 and ribosomal protein RPS10 as direct ubiquitylation substrates of MKRN1. Conclusions We propose that MKRN1 mediates the recognition of poly(A) tails to prevent the production of erroneous proteins from prematurely polyadenylated transcripts, thereby maintaining proteome integrity.

scholarly journals Polyamines as Quality Control Metabolites Operating at the Post-Transcriptional Level

Plants ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 109 ◽  
Author(s):  
Laetitia Poidevin ◽  
Dilek Unal ◽  
Borja Belda-Palazón ◽  
Alejandro Ferrando
Keyword(s):  
Quality Control ◽  
Molecular Mechanisms ◽  
Transcriptional Level ◽  
Control Mechanisms ◽  
Physiological Functions ◽  
Nonsense Mediated Decay ◽  
Stop Codons ◽  
Ribosome Stalling ◽  
Molecular Functions

Plant polyamines (PAs) have been assigned a large number of physiological functions with unknown molecular mechanisms in many cases. Among the most abundant and studied polyamines, two of them, namely spermidine (Spd) and thermospermine (Tspm), share some molecular functions related to quality control pathways for tightly regulated mRNAs at the level of translation. In this review, we focus on the roles of Tspm and Spd to facilitate the translation of mRNAs containing upstream ORFs (uORFs), premature stop codons, and ribosome stalling sequences that may block translation, thus preventing their degradation by quality control mechanisms such as the nonsense-mediated decay pathway and possible interactions with other mRNA quality surveillance pathways.

scholarly journals The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Aitor Garzia ◽  
Seyed Mehdi Jafarnejad ◽  
Cindy Meyer ◽  
Clément Chapat ◽  
Tasos Gogakos ◽  
...  
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
E3 Ubiquitin Ligase

scholarly journals MAPK signaling couples SCF-mediated degradation of translational regulators to oocyte meiotic progression

2018 ◽  
Vol 115 (12) ◽  
pp. E2772-E2781 ◽  
Author(s):  
Edyta Kisielnicka ◽  
Ryuji Minasaki ◽  
Christian R. Eckmann
Keyword(s):  
Gene Expression ◽  
Ubiquitin Ligase ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mapk Signaling ◽  
Negative Control ◽  
Molecular Scaffold ◽  
Meiotic Progression ◽  
Ubiquitin Ligase Complex ◽  
Translational Regulators

RNA-binding proteins (RBPs) are important regulators of gene expression programs, especially during gametogenesis. How the abundance of particular RBPs is restricted to defined stages of meiosis remains largely elusive. Here, we report a molecular pathway that subjects two nonrelated but broadly evolutionarily conserved translational regulators (CPB-3/CPEB and GLD-1/STAR) to proteosomal degradation in Caenorhabditis elegans germ cells at the transition from pachytene to diplotene of meiotic prophase. Both RBPs are recognized by the same ubiquitin ligase complex, containing the molecular scaffold Cullin-1 and the tumor suppressor SEL-10/FBXW7 as its substrate recognition subunit. Destabilization of either RBP through this Skp, Cullin, F-box–containing complex (SCF) ubiquitin ligase appears to loosen its negative control over established target mRNAs, and presumably depends on a prior phosphorylation of CPB-3 and GLD-1 by MAPK (MPK-1), whose activity increases in mid- to late pachytene to promote meiotic progression and oocyte differentiation. Thus, we propose that the orchestrated degradation of RBPs via MAPK-signaling cascades during germ cell development may act to synchronize meiotic with sexual differentiation gene expression changes.

scholarly journals APE1/Ref-1 Interacts with NPM1 within Nucleoli and Plays a Role in the rRNA Quality Control Process

2009 ◽  
Vol 29 (7) ◽  
pp. 1834-1854 ◽  
Author(s):  
Carlo Vascotto ◽  
Damiano Fantini ◽  
Milena Romanello ◽  
Laura Cesaratto ◽  
Marta Deganuto ◽  
...  
Keyword(s):  
Quality Control ◽  
Cell Growth ◽  
Ribosome Biogenesis ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rrna Synthesis ◽  
Control Mechanisms ◽  
Endonuclease Activity ◽  
Proteomic Approach ◽  
Quality Control Process

ABSTRACT APE1/Ref-1 (hereafter, APE1), a DNA repair enzyme and a transcriptional coactivator, is a vital protein in mammals. Its role in controlling cell growth and the molecular mechanisms that fine-tune its different cellular functions are still not known. By an unbiased proteomic approach, we have identified and characterized several novel APE1 partners which, unexpectedly, include a number of proteins involved in ribosome biogenesis and RNA processing. In particular, a novel interaction between nucleophosmin (NPM1) and APE1 was characterized. We observed that the 33 N-terminal residues of APE1 are required for stable interaction with the NPM1 oligomerization domain. As a consequence of the interaction with NPM1 and RNA, APE1 is localized within the nucleolus and this localization depends on cell cycle and active rRNA transcription. NPM1 stimulates APE1 endonuclease activity on abasic double-stranded DNA (dsDNA) but decreases APE1 endonuclease activity on abasic single-stranded RNA (ssRNA) by masking the N-terminal region of APE1 required for stable RNA binding. In APE1-knocked-down cells, pre-rRNA synthesis and rRNA processing were not affected but inability to remove 8-hydroxyguanine-containing rRNA upon oxidative stress, impaired translation, lower intracellular protein content, and decreased cell growth rate were found. Our data demonstrate that APE1 affects cell growth by directly acting on RNA quality control mechanisms, thus affecting gene expression through posttranscriptional mechanisms.

scholarly journals The RNA-binding protein HuR is a novel target of Pirh2 E3 ubiquitin ligase

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Alexandra Daks ◽  
Alexey Petukhov ◽  
Olga Fedorova ◽  
Oleg Shuvalov ◽  
Alena Kizenko ◽  
...  
Keyword(s):  
Heat Shock ◽  
Ubiquitin Ligase ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
P53 Family ◽  
Associated Proteins ◽  
Novel Target

AbstractThe RING-finger protein Pirh2 is a p53 family-specific E3 ubiquitin ligase. Pirh2 also ubiquitinates several other important cellular factors and is involved in carcinogenesis. However, its functional role in other cellular processes is poorly understood. To address this question, we performed a proteomic search for novel interacting partners of Pirh2. Using the GST-pulldown approach combined with LC-MS/MS, we revealed 225 proteins that interacted with Pirh2. We found that, according to the GO description, a large group of Pirh2-associated proteins belonged to the RNA metabolism group. Importantly, one of the identified proteins from that group was an RNA-binding protein ELAVL1 (HuR), which is involved in the regulation of splicing and protein stability of several oncogenic proteins. We demonstrated that Pirh2 ubiquitinated the HuR protein facilitating its proteasome-mediated degradation in cells. Importantly, the Pirh2-mediated degradation of HuR occurred in response to heat shock, thereby affecting the survival rate of HeLa cells under elevated temperature. Functionally, Pirh2-mediated degradation of HuR augmented the level of c-Myc expression, whose RNA level is otherwise attenuated by HuR. Taken together, our data indicate that HuR is a new target of Pirh2 and this functional interaction contributes to the heat-shock response of cancer cells affecting their survival.

scholarly journals The ribosome-bound quality control complex remains associated to aberrant peptides during their proteasomal targeting and interacts with Tom1 to limit protein aggregation

2017 ◽  
Vol 28 (9) ◽  
pp. 1165-1176 ◽  
Author(s):  
Quentin Defenouillère ◽  
Abdelkader Namane ◽  
John Mouaikel ◽  
Alain Jacquier ◽  
Micheline Fromont-Racine
Keyword(s):  
Quality Control ◽  
Protein Aggregation ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Translation Termination ◽  
E3 Ubiquitin Ligase ◽  
Protein Quality Control ◽  
Control Mechanisms ◽  
Ubiquitin Ligase Activity ◽  
Control Complex

Protein quality control mechanisms eliminate defective polypeptides to ensure proteostasis and to avoid the toxicity of protein aggregates. In eukaryotes, the ribosome-bound quality control (RQC) complex detects aberrant nascent peptides that remain stalled in 60S ribosomal particles due to a dysfunction in translation termination. The RQC complex polyubiquitylates aberrant polypeptides and recruits a Cdc48 hexamer to extract them from 60S particles in order to escort them to the proteasome for degradation. Whereas the steps from stalled 60S recognition to aberrant peptide polyubiquitylation by the RQC complex have been described, the mechanism leading to proteasomal degradation of these defective translation products remains unknown. We show here that the RQC complex also exists as a ribosome-unbound complex during the escort of aberrant peptides to the proteasome. In addition, we identify a new partner of this light version of the RQC complex, the E3 ubiquitin ligase Tom1. Tom1 interacts with aberrant nascent peptides and is essential to limit their accumulation and aggregation in the absence of Rqc1; however, its E3 ubiquitin ligase activity is not required. Taken together, these results reveal new roles for Tom1 in protein quality control, aggregate prevention, and, therefore, proteostasis maintenance.

scholarly journals Quality Control Mechanisms in Bacterial Translation

Acta Naturae ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 32-44
Author(s):  
Anastasiia S. Zarechenskaia ◽  
Petr V. Sergiev ◽  
Ilya A. Osterman
Keyword(s):  
Quality Control ◽  
Cell Viability ◽  
Functional Role ◽  
Control Mechanisms ◽  
Cultivation Conditions ◽  
Ribosome Stalling ◽  
Hydrolysis Of ◽  
Bacterial Translation

Ribosome stalling during translation significantly reduces cell viability, because cells have to spend resources on the synthesis of new ribosomes. Therefore, all bacteria have developed various mechanisms of ribosome rescue. Usually, the release of ribosomes is preceded by hydrolysis of the tRNApeptide bond, but, in some cases, the ribosome can continue translation thanks to the activity of certain factors. This review describes the mechanisms of ribosome rescue thanks to trans-translation and the activity of the ArfA, ArfB, BrfA, ArfT, HflX, and RqcP/H factors, as well as continuation of translation via the action of EF-P, EF-4, and EttA. Despite the ability of some systems to duplicate each other, most of them have their unique functional role, related to the quality control of bacterial translation in certain abnormalities caused by mutations, stress cultivation conditions, or antibiotics.

Cytosolic protein quality control machinery: Interactions of Hsp70 with a network of co-chaperones and substrates

2021 ◽  
pp. 153537022199981
Author(s):  
Chamithi Karunanayake ◽  
Richard C Page
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Structural Features ◽  
Cellular Protein ◽  
Mechanisms Of Action ◽  
Control Mechanisms ◽  
Nucleotide Exchange ◽  
Domain Organization ◽  
Nucleotide Exchange Factors

The chaperone heat shock protein 70 (Hsp70) and its network of co-chaperones serve as a central hub of cellular protein quality control mechanisms. Domain organization in Hsp70 dictates ATPase activity, ATP dependent allosteric regulation, client/substrate binding and release, and interactions with co-chaperones. The protein quality control activities of Hsp70 are classified as foldase, holdase, and disaggregase activities. Co-chaperones directly assisting protein refolding included J domain proteins and nucleotide exchange factors. However, co-chaperones can also be grouped and explored based on which domain of Hsp70 they interact. Here we discuss how the network of cytosolic co-chaperones for Hsp70 contributes to the functions of Hsp70 while closely looking at their structural features. Comparison of domain organization and the structures of co-chaperones enables greater understanding of the interactions, mechanisms of action, and roles played in protein quality control.

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