Nuclear mRNA Quality Control and Cytoplasmic NMD Are Linked by the Guard Proteins Gbp2 and Hrb1

Pre-mRNA splicing is critical for cells, as defects in this process can lead to altered open reading frames and defective proteins, potentially causing neurodegenerative diseases and cancer. Introns are removed in the nucleus and splicing is documented by the addition of exon-junction-complexes (EJCs) at exon-exon boundaries. This “memory” of splicing events is important for the ribosome, which translates the RNAs in the cytoplasm. In case a stop codon was detected before an EJC, translation is blocked and the RNA is eliminated by the nonsense-mediated decay (NMD). In the model organism Saccharomyces cerevisiae, two guard proteins, Gbp2 and Hrb1, have been identified as nuclear quality control factors for splicing. In their absence, intron-containing mRNAs leak into the cytoplasm. Their presence retains transcripts until the process is completed and they release the mRNAs by recruitment of the export factor Mex67. On transcripts that experience splicing problems, these guard proteins recruit the nuclear RNA degradation machinery. Interestingly, they continue their quality control function on exported transcripts. They support NMD by inhibiting translation and recruiting the cytoplasmic degradation factors. In this way, they link the nuclear and cytoplasmic quality control systems. These discoveries are also intriguing for humans, as homologues of these guard proteins are present also in multicellular organisms. Here, we provide an overview of the quality control mechanisms of pre-mRNA splicing, and present Gbp2 and Hrb1, as well as their human counterparts, as important players in these pathways.

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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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Regulation of gene expression in mammalian nervous system through alternative pre-mRNA splicing coupled with RNA quality control mechanisms

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2013.01.003 ◽

2013 ◽

Vol 56 ◽

pp. 420-428 ◽

Cited By ~ 49

Author(s):

Karen Yap ◽

Eugene V. Makeyev

Keyword(s):

Gene Expression ◽

Quality Control ◽

Nervous System ◽

Regulation Of Gene Expression ◽

Mrna Splicing ◽

Control Mechanisms ◽

Rna Quality ◽

Rna Quality Control

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Quality control of protein import into mitochondria

Biochemical Journal ◽

10.1042/bcj20190584 ◽

2021 ◽

Vol 478 (16) ◽

pp. 3125-3143

Author(s):

Fabian den Brave ◽

Jeannine Engelke ◽

Thomas Becker

Keyword(s):

Quality Control ◽

Stress Responses ◽

Protein Transport ◽

Protein Import ◽

Mitochondrial Protein ◽

Control Mechanisms ◽

Unfolded Proteins ◽

Control Factors ◽

Precursor Proteins ◽

Cellular Stress Responses

Mitochondria import about 1000 proteins that are produced as precursors on cytosolic ribosomes. Defects in mitochondrial protein import result in the accumulation of non-imported precursor proteins and proteotoxic stress. The cell is equipped with different quality control mechanisms to monitor protein transport into mitochondria. First, molecular chaperones guide unfolded proteins to mitochondria and deliver non-imported proteins to proteasomal degradation. Second, quality control factors remove translocation stalled precursor proteins from protein translocases. Third, protein translocases monitor protein sorting to mitochondrial subcompartments. Fourth, AAA proteases of the mitochondrial subcompartments remove mislocalized or unassembled proteins. Finally, impaired efficiency of protein transport is an important sensor for mitochondrial dysfunction and causes the induction of cellular stress responses, which could eventually result in the removal of the defective mitochondria by mitophagy. In this review, we summarize our current understanding of quality control mechanisms that govern mitochondrial protein transport.

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Global Analysis of mRNA Decay in Halobacterium salinarum NRC-1 at Single-Gene Resolution Using DNA Microarrays

Journal of Bacteriology ◽

10.1128/jb.00559-07 ◽

2007 ◽

Vol 189 (19) ◽

pp. 6936-6944 ◽

Cited By ~ 24

Author(s):

Sonja Hundt ◽

Alexander Zaigler ◽

Christian Lange ◽

Jörg Soppa ◽

Gabriele Klug

Keyword(s):

Dna Microarrays ◽

Global Analysis ◽

Single Gene ◽

Regulation Of Gene Expression ◽

Model Organism ◽

Rna Degradation ◽

Halobacterium Salinarum ◽

Open Reading Frames ◽

Transcript Stability ◽

The Stability

ABSTRACT RNA degradation is an important factor in the regulation of gene expression. It allows organisms to quickly respond to changing environmental conditions by adapting the expression of individual genes. The stability of individual mRNAs within an organism varies considerably, contributing to differential amounts of proteins expressed. In this study we used DNA microarrays to analyze mRNA degradation in exponentially growing cultures of the extremely halophilic euryarchaeon Halobacterium salinarum NRC-1 on a global level. We determined mRNA half-lives for 1,717 open reading frames, 620 of which are part of known or predicted operons. Under the tested conditions transcript stabilities ranged from 5 min to more than 18 min, with 79% of the evaluated mRNAs showing half-lives between 8 and 12 min. The overall mean half-life was 10 min, which is considerably longer than the ones found in the other prokaryotes investigated thus far. As previously observed in Escherichia coli and Saccharomyces cerevisiae, we could not detect a significant correlation between transcript length and transcript stability, but there was a relationship between gene function and transcript stability. Genes that are known or predicted to be transcribed in operons exhibited similar mRNA half-lives. These results provide initial insights into mRNA turnover in a euryarchaeon. Moreover, our model organism, H. salinarum NRC-1, is one of just two archaea sequenced to date that are missing the core subunits of the archaeal exosome. This complex orthologous to the RNA degrading exosome of eukarya is found in all other archaeal genomes sequenced thus far.

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The Host Cell’s Endoplasmic Reticulum Proteostasis Network Profoundly Shapes the Protein Sequence Space Accessible to HIV Envelope

10.1101/2021.04.24.441266 ◽

2021 ◽

Author(s):

Jimin Yoon ◽

Emmanuel E. Nekongo ◽

Jessica E. Patrick ◽

Angela M. Phillips ◽

Anna I. Ponomarenko ◽

...

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Sequence Space ◽

Protein Sequence ◽

Neutralizing Antibodies ◽

Control Mechanisms ◽

Control Factors ◽

The Unfolded Protein Response ◽

Hiv Envelope ◽

Protein Sequence Space

AbstractThe sequence space accessible to evolving proteins can be enhanced by cellular chaperones that assist biophysically defective clients in navigating complex folding landscapes. It is also possible, however, for proteostasis mechanisms that promote strict quality control to greatly constrain accessible protein sequence space. Unfortunately, most efforts to understand how proteostasis mechanisms influence evolution rely on artificial inhibition or genetic knockdown of specific chaperones. The few experiments that perturb quality control pathways also generally modulate the levels of only individual quality control factors. Here, we use chemical genetic strategies to tune proteostasis networks via natural stress response pathways that regulate levels of entire suites of chaperones and quality control mechanisms. Specifically, we upregulate the unfolded protein response (UPR) to test the hypothesis that the host endoplasmic reticulum (ER) proteostasis network shapes the sequence space accessible to human immunodeficiency virus-1 (HIV) envelope (Env) protein. Elucidating factors that enhance or constrain Env sequence space is critical because Env evolves extremely rapidly, yielding HIV strains with antibody and drug escape mutations. We find that UPR-mediated upregulation of ER proteostasis factors, particularly those controlled by the IRE1-XBP1s UPR arm, globally reduces Env mutational tolerance. Conserved, functionally important Env regions exhibit the largest decreases in mutational tolerance upon XBP1s activation. This phenomenon likely reflects strict quality control endowed by XBP1s-mediated remodeling of the ER proteostasis environment. Intriguingly and in contrast, specific regions of Env, including regions targeted by broadly neutralizing antibodies, display enhanced mutational tolerance when XBP1s is activated, hinting at a role for host proteostasis network hijacking in potentiating antibody escape. These observations reveal a key function for proteostasis networks in decreasing instead of expanding the sequence space accessible to client proteins, while also demonstrating that the host ER proteostasis network profoundly shapes the mutational tolerance of Env in ways that could have important consequences for HIV adaptation.

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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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Temperature and UV light affect the activity of marine cell-free enzymes

Biogeosciences ◽

10.5194/bg-14-3971-2017 ◽

2017 ◽

Vol 14 (17) ◽

pp. 3971-3977 ◽

Cited By ~ 3

Author(s):

Blair Thomson ◽

Christopher David Hepburn ◽

Miles Lamare ◽

Federico Baltar

Keyword(s):

Organic Matter ◽

Extracellular Enzymes ◽

Elevated Temperatures ◽

Uv Light ◽

Control Mechanisms ◽

Potential Control ◽

Control Factors ◽

Rate Limiting Step ◽

Ocean Environment ◽

First Time

Abstract. Microbial extracellular enzymatic activity (EEA) is the rate-limiting step in the degradation of organic matter in the oceans. These extracellular enzymes exist in two forms: cell-bound, which are attached to the microbial cell wall, and cell-free, which are completely free of the cell. Contrary to previous understanding, cell-free extracellular enzymes make up a substantial proportion of the total marine EEA. Little is known about these abundant cell-free enzymes, including what factors control their activity once they are away from their sites (cells). Experiments were run to assess how cell-free enzymes (excluding microbes) respond to ultraviolet radiation (UVR) and temperature manipulations, previously suggested as potential control factors for these enzymes. The experiments were done with New Zealand coastal waters and the enzymes studied were alkaline phosphatase (APase), β-glucosidase, (BGase), and leucine aminopeptidase (LAPase). Environmentally relevant UVR (i.e. in situ UVR levels measured at our site) reduced cell-free enzyme activities by up to 87 % when compared to controls, likely a consequence of photodegradation. This effect of UVR on cell-free enzymes differed depending on the UVR fraction. Ambient levels of UV radiation were shown to reduce the activity of cell-free enzymes for the first time. Elevated temperatures (15 °C) increased the activity of cell-free enzymes by up to 53 % when compared to controls (10 °C), likely by enhancing the catalytic activity of the enzymes. Our results suggest the importance of both UVR and temperature as control mechanisms for cell-free enzymes. Given the projected warming ocean environment and the variable UVR light regime, it is possible that there could be major changes in the cell-free EEA and in the enzymes contribution to organic matter remineralization in the future.

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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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