Coupling of translation quality control and mRNA targeting to stress granules

Stress granules are dynamic assemblies of proteins and nontranslating RNAs that form when translation is inhibited in response to diverse stresses. Defects in ubiquitin–proteasome system factors including valosin-containing protein (VCP) and the proteasome impact the kinetics of stress granule induction and dissolution as well as being implicated in neuropathogenesis. However, the impacts of dysregulated proteostasis on mRNA regulation and stress granules are not well understood. Using single mRNA imaging, we discovered ribosomes stall on some mRNAs during arsenite stress, and the release of transcripts from stalled ribosomes for their partitioning into stress granules requires the activities of VCP, components of the ribosome-associated quality control (RQC) complex, and the proteasome. This is an unexpected contribution of the RQC system in releasing mRNAs from translation under stress, thus identifying a new type of stress-activated RQC (saRQC) distinct from canonical RQC pathways in mRNA substrates, cellular context, and mRNA fate.

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Coupling of translation quality control and mRNA targeting to stress granules

10.1101/2020.01.05.895342 ◽

2020 ◽

Cited By ~ 2

Author(s):

Stephanie L. Moon ◽

Tatsuya Morisaki ◽

Timothy J. Stasevich ◽

Roy Parker

Keyword(s):

Quality Control ◽

Acute Stress ◽

Mrna Translation ◽

Stress Granules ◽

Live Cells ◽

Translation Quality ◽

Cellular Context ◽

Ubiquitin Proteasome ◽

New Type ◽

Mrna Targeting

AbstractStress granules (SGs) are dynamic assemblies of non-translating RNAs and proteins that form with translation inhibition1. Stress granules are similar to neuronal and germ cell granules, play a role in survival during stress, and aberrant, cytotoxic SGs are implicated in neurodegeneration2–4. Perturbations in the ubiquitin-proteasome (UPS) system also cause neurodegeneration5–10, and alter the dynamicity and kinetics of SGs11–14. Using single mRNA imaging in live cells15, 16, we took an unbiased approach to determine if defects in the UPS perturb mRNA translation and partitioning into SGs during acute stress. We observe ribosomes stall on mRNAs during arsenite stress, and the release of transcripts from stalled ribosomes for their partitioning into SGs requires the activities of valosin-containing protein (VCP) and the proteasome, which is in contrast to previous work showing VCP primarily affected SG disassembly 11, 13, 14, 17. Moreover, members of a specialized complex in the UPS that targets aberrant nascent proteins for decay upon ribosome stalling, referred to as ribosome-associated quality control complex (RQC)18, are also required for mRNA release from ribosomes and partitioning into SGs. VCP alleles that increase segregase activity and cause neurodegeneration and inclusion body myopathies5, 6, 19, 20 increase mRNA recruitment to SGs, suggesting aberrant mRNA localization to SGs in disease contexts. This work identifies a new type of stress-activated RQC (saRQC) distinct from canonical RQC pathways in mRNA substrates, cellular context and mRNA fate.

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Coupling of translation quality control and mRNA targeting to stress granules

10.26226/morressier.5ebd45acffea6f735881af0e ◽

2020 ◽

Author(s):

Stephanie Moon

Keyword(s):

Quality Control ◽

Stress Granules ◽

Translation Quality ◽

Mrna Targeting

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The role of the ubiquitin–proteasome system in ER quality control

Essays in Biochemistry ◽

10.1042/eb0410099 ◽

2005 ◽

Vol 41 (1) ◽

pp. 99 ◽

Cited By ~ 10

Author(s):

Yihong Ye

Keyword(s):

Quality Control ◽

Ubiquitin Proteasome System ◽

Er Quality Control ◽

Ubiquitin Proteasome

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TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

Cellular and Molecular Neurobiology ◽

10.1007/s10571-021-01060-z ◽

2021 ◽

Author(s):

Xu Zhou ◽

Xiongjin Chen ◽

Tingting Hong ◽

Miaoping Zhang ◽

Yujie Cai ◽

...

Keyword(s):

Quality Control ◽

Cognitive Impairment ◽

Protein Quality ◽

Protein Quality Control ◽

Ubiquitin Proteasome System ◽

Research Progress ◽

Repeat Domain ◽

Ubiquitin Proteasome ◽

Domain 3

AbstractThe tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

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Increasing autophagy does not affect neurogenic muscle atrophy

European Journal of Translational Myology ◽

10.4081/ejtm.2018.7687 ◽

2018 ◽

Vol 28 (3) ◽

Cited By ~ 5

Author(s):

Eva Pigna ◽

Krizia Sanna ◽

Dario Coletti ◽

Zhenlin Li ◽

Ara Parlakian ◽

...

Keyword(s):

Muscle Mass ◽

Muscle Atrophy ◽

Ubiquitin Proteasome System ◽

Autophagic Flux ◽

Molecular Pathways ◽

Muscle Loss ◽

Relative Contribution ◽

Ubiquitin Proteasome ◽

Muscle Mass Loss ◽

Kinetics Of

Physiological autophagy plays a crucial role in the regulation of muscle mass and metabolism, while the excessive induction or the inhibition of the autophagic flux contributes to the progression of several diseases. Autophagy can be activated by different stimuli, including cancer, exercise, caloric restriction and denervation. The latter leads to muscle atrophy through the activation of catabolic pathways, i.e. the ubiquitin-proteasome system and autophagy. However, the kinetics of autophagy activation and the upstream molecular pathways in denervated skeletal muscle have not been reported yet. In this study, we characterized the kinetics of autophagic induction, quickly triggered by denervation, and report the Akt/mTOR axis activation. Besides, with the aim to assess the relative contribution of autophagy in neurogenic muscle atrophy, we triggered autophagy with different stimuli along with denervation, and observed that four week-long autophagic induction, by either intermitted fasting or rapamycin treatment, did not significantly affect muscle mass loss. We conclude that: i) autophagy does not play a major role in inducing muscle loss following denervation; ii) nonetheless, autophagy may have a regulatory role in denervation induced muscle atrophy, since it is significantly upregulated as early as eight hours after denervation; iii) Akt/mTOR axis, AMPK and FoxO3a are activated consistently with the progression of muscle atrophy, further highlighting the complexity of the signaling response to the atrophying stimulus deriving from denervation.

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Protein Quality Control in Neurodegeneration and Neuroprotection

Quality Control of Cellular Protein in Neurodegenerative Disorders - Advances in Medical Diagnosis, Treatment, and Care ◽

10.4018/978-1-7998-1317-0.ch001 ◽

2020 ◽

pp. 1-24

Author(s):

Yasmeena Akhter ◽

Jahangir Nabi ◽

Hinna Hamid ◽

Nahida Tabassum ◽

Faheem Hyder Pottoo ◽

...

Keyword(s):

Quality Control ◽

Neurodegenerative Disorders ◽

Protein Quality ◽

Protein Quality Control ◽

Ubiquitin Proteasome System ◽

Security System ◽

Conformational Disorders ◽

Ubiquitin Proteasome ◽

Multi Level

Proteostasis is essential for regulating the integrity of the proteome. Disruption of proteostasis under some rigorous conditions leads to the aggregation and accumulation of misfolded toxic proteins, which plays a central role in the pathogenesis of protein conformational disorders. The protein quality control (PQC) system serves as a multi-level security system to shield cells from abnormal proteins. The intrinsic PQC systems maintaining proteostasis include the ubiquitin-proteasome system (UPS), chaperon-mediated autophagy (CMA), and autophagy-lysosome pathway (ALP) that serve to target misfolded proteins for unfolding, refolding, or degradation. Alterations of PQC systems in neurons have been implicated in the pathogenesis of various neurodegenerative disorders. This chapter provides an overview of PQC pathways to set a framework for discussion of the role of PQC in neurodegenerative disorders. Additionally, various pharmacological approaches targeting PQC are summarized.

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