Quality Control Mechanisms in 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.

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Abstract P049: Circadian Clock Dysfunction Impairs Mitochondrial Fitness And Contributes To Myocardial Ischemic Injury

Hypertension ◽

10.1161/hyp.76.suppl_1.p049 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Inna Rabinovich-Nikitin ◽

Illana Posen ◽

Victoria Margulets ◽

Tami A Martino ◽

Lorrie A Kirshenbaum

Keyword(s):

Quality Control ◽

Cell Viability ◽

Circadian Clock ◽

Cardiac Myocytes ◽

Mitochondrial Dynamics ◽

Ischemia Reperfusion ◽

Mitochondrial Fission ◽

Control Mechanisms ◽

Complex Activity ◽

Mitochondrial Dynamic

Cardiac function is highly reliant on mitochondrial oxidative metabolism and fitness. The circadian clock is critically linked to vital physiological process including mitochondrial fission, fusion and quality control mechanisms. However, little is known of how the circadian clock regulates these vital processes in the heart. Herein, we identified a putative circadian Clock - mitochondrial interactome that gates an adaptive stress response for cell viability during myocardial ischemia reperfusion (I-R) injury. We show that Clock transcriptionally coordinates expression of mitochondrial dynamic fusion and fission, bioenergetic and quality control proteins in cardiac myocytes. Transcriptome and gene ontology mapping revealed Clock defective hearts subjected to I-R exhibited major transcriptional deficits in several key survival processes including mitochondrial dynamics, bioenergetics and autophagy that were reduced further following I-R. Gain of function of Clock activity re-established gene transcription of mitochondrial respiratory complex activity, quality control mechanisms and cell viability. Collectively, our data show that mitochondrial fitness and cell survival is mutually dependent upon and obligatorily linked to transcription of the circadian Clock gene in cardiac myocytes. Our data suggest the functional loss of Clock activity predisposes cardiac myocytes to metabolic catastrophe. Hence, therapeutic strategies designed to preserve circadian clock activity in the hearts may prove beneficial in reducing morbidity and mortality following ischemia -related pathologies such as myocardial infarction.

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

Plants ◽

10.3390/plants8040109 ◽

2019 ◽

Vol 8 (4) ◽

pp. 109 ◽

Cited By ~ 4

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.

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

10.1101/516005 ◽

2019 ◽

Cited By ~ 1

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.

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

Genome Biology ◽

10.1186/s13059-019-1814-0 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 11

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.

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Quality controls induced by aberrant translation

Nucleic Acids Research ◽

10.1093/nar/gkz1201 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1084-1096 ◽

Cited By ~ 11

Author(s):

Toshifumi Inada

Keyword(s):

Quality Control ◽

Protein Synthesis ◽

Cell Viability ◽

Control Systems ◽

Polypeptide Chain ◽

Translation Product ◽

Regulatory Factors ◽

Nascent Polypeptide ◽

Quality Controls ◽

Ribosome Stalling

Abstract During protein synthesis, translating ribosomes encounter many challenges imposed by various types of defective mRNAs that can lead to reduced cellular fitness and, in some cases, even threaten cell viability. Aberrant translation leads to activation of one of several quality control pathways depending on the nature of the problem. These pathways promote the degradation of the problematic mRNA as well as the incomplete translation product, the nascent polypeptide chain. Many of these quality control systems feature critical roles for specialized regulatory factors that work in concert with conventional factors. This review focuses on the mechanisms used by these quality control pathways to recognize aberrant ribosome stalling and discusses the conservation of these systems.

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

Experimental Biology and Medicine ◽

10.1177/1535370221999812 ◽

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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COVID-19 Brings Data Equity Challenges to the Fore

Digital Government: Research and Practice (DGOV) ◽

10.1145/3440889 ◽

2021 ◽

Author(s):

H.V. Jagadish ◽

Julia Stoyanovich ◽

Bill Howe

Keyword(s):

Quality Control ◽

Government Policy ◽

Data Driven ◽

Contact Tracing ◽

Control Mechanisms ◽

Sources Of Information ◽

Decision Systems ◽

Physical Resources ◽

Multiple Levels ◽

Data Driven Decisions

The COVID-19 pandemic is compelling us to make crucial data-driven decisions quickly, bringing together diverse and unreliable sources of information without the usual quality control mechanisms we may employ. These decisions are consequential at multiple levels: they can inform local, state and national government policy, be used to schedule access to physical resources such as elevators and workspaces within an organization, and inform contact tracing and quarantine actions for individuals. In all these cases, significant inequities are likely to arise, and to be propagated and reinforced by data-driven decision systems. In this article, we propose a framework, called FIDES, for surfacing and reasoning about data equity in these systems.

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NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease

Nature Communications ◽

10.1038/s41467-020-18327-6 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 3

Author(s):

Paige B. Martin ◽

Yu Kigoshi-Tansho ◽

Roger B. Sher ◽

Gianina Ravenscroft ◽

Jennifer E. Stauffer ◽

...

Keyword(s):

Quality Control ◽

Nervous System ◽

Mouse Models ◽

Human Disease ◽

Neuromuscular Disease ◽

Protein Quality ◽

Protein Quality Control ◽

Motor Neuron Degeneration ◽

Neuron Degeneration ◽

Ribosome Stalling

Abstract A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway—Ribosome-associated Quality Control (RQC)—by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF’s role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.

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Limited ER quality control for GPI-anchored proteins

The Journal of Cell Biology ◽

10.1083/jcb.201602010 ◽

2016 ◽

Vol 213 (6) ◽

pp. 693-704 ◽

Cited By ~ 22

Author(s):

Natalia Sikorska ◽

Leticia Lemus ◽

Auxiliadora Aguilera-Romero ◽

Javier Manzano-Lopez ◽

Howard Riezman ◽

...

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Protein Folding ◽

Misfolded Proteins ◽

Control Mechanisms ◽

Gpi Anchor ◽

Er Quality Control ◽

Entire Class ◽

Er Export ◽

Export Signal

Endoplasmic reticulum (ER) quality control mechanisms target terminally misfolded proteins for ER-associated degradation (ERAD). Misfolded glycophosphatidylinositol-anchored proteins (GPI-APs) are, however, generally poor ERAD substrates and are targeted mainly to the vacuole/lysosome for degradation, leading to predictions that a GPI anchor sterically obstructs ERAD. Here we analyzed the degradation of the misfolded GPI-AP Gas1* in yeast. We could efficiently route Gas1* to Hrd1-dependent ERAD and provide evidence that it contains a GPI anchor, ruling out that a GPI anchor obstructs ERAD. Instead, we show that the normally decreased susceptibility of Gas1* to ERAD is caused by canonical remodeling of its GPI anchor, which occurs in all GPI-APs and provides a protein-independent ER export signal. Thus, GPI anchor remodeling is independent of protein folding and leads to efficient ER export of even misfolded species. Our data imply that ER quality control is limited for the entire class of GPI-APs, many of them being clinically relevant.

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