Protein quality control in the secretory pathway

Sun, Zhihao; Brodsky, Jeffrey L.

doi:10.1083/jcb.201906047

Cited by 291 publications

(309 citation statements)

References 243 publications

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“…Several systems exist to degrade defective proteins. Among them are cytosolic ubiquitin/proteasome system, endoplasmic reticulum associated degradation (ERAD), and the unfolded protein response (UPR) [39][40][41][42][43][44]. These pathways sense and destroy misfolded or aberrant proteins that are already synthesized and need to be removed.…”

Section: Quality Control Of Mrnas and Proteins During Translationmentioning

confidence: 99%

Translational Control of Secretory Proteins in Health and Disease

Karamyshev

Tikhonova

Karamysheva

2020

IJMS

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Secretory proteins are synthesized in a form of precursors with additional sequences at their N-terminal ends called signal peptides. The signal peptides are recognized co-translationally by signal recognition particle (SRP). This interaction leads to targeting to the endoplasmic reticulum (ER) membrane and translocation of the nascent chains into the ER lumen. It was demonstrated recently that in addition to a targeting function, SRP has a novel role in protection of secretory protein mRNAs from degradation. It was also found that the quality of secretory proteins is controlled by the recently discovered Regulation of Aberrant Protein Production (RAPP) pathway. RAPP monitors interactions of polypeptide nascent chains during their synthesis on the ribosomes and specifically degrades their mRNAs if these interactions are abolished due to mutations in the nascent chains or defects in the targeting factor. It was demonstrated that pathological RAPP activation is one of the molecular mechanisms of human diseases associated with defects in the secretory proteins. In this review, we discuss recent progress in understanding of translational control of secretory protein biogenesis on the ribosome and pathological consequences of its dysregulation in human diseases.

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Section: Quality Control Of Mrnas and Proteins During Translationmentioning

confidence: 99%

Translational Control of Secretory Proteins in Health and Disease

Karamyshev

Tikhonova

Karamysheva

2020

IJMS

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“…After exiting the ER, properly folded membrane proteins are packaged into ER-derived transport vesicles and then delivered to the Golgi apparatus, wherein proteins are subject to further maturation and glycosylation. Significantly, membrane proteins are also subject to a rigorous quality control at the Golgi (114,115,122). In general, during this membrane trafficking process, transport vesicles are progressively transferred through the ER-Golgi intermediate compartment, the cis-Golgi network, the Golgi stack (cis-, medial-, and trans-Golgi compartments), and finally to the trans-Golgi network, from which mature proteins are shipped to the plasma membrane [ Figure 2B; (123)(124)(125)(126)].…”

Section: Myotonia-associated Disruption Of Human Clc-1 Proteostasismentioning

confidence: 99%

Defective Gating and Proteostasis of Human ClC-1 Chloride Channel: Molecular Pathophysiology of Myotonia Congenita

Jeng¹,

You

et al. 2020

Front. Neurol.

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The voltage-dependent ClC-1 chloride channel, whose open probability increases with membrane potential depolarization, belongs to the superfamily of CLC channels/transporters. ClC-1 is almost exclusively expressed in skeletal muscles and is essential for stabilizing the excitability of muscle membranes. Elucidation of the molecular structures of human ClC-1 and several CLC homologs provides important insight to the gating and ion permeation mechanisms of this chloride channel. Mutations in the human CLCN1 gene, which encodes the ClC-1 channel, are associated with a hereditary skeletal muscle disease, myotonia congenita. Most disease-causing CLCN1 mutations lead to loss-of-function phenotypes in the ClC-1 channel and thus increase membrane excitability in skeletal muscles, consequently manifesting as delayed relaxations following voluntary muscle contractions in myotonic subjects. The inheritance pattern of myotonia congenita can be autosomal dominant (Thomsen type) or recessive (Becker type). To date over 200 myotonia-associated ClC-1 mutations have been identified, which are scattered throughout the entire protein sequence. The dominant inheritance pattern of some myotonia mutations may be explained by a dominant-negative effect on ClC-1 channel gating. For many other myotonia mutations, however, no clear relationship can be established between the inheritance pattern and the location of the mutation in the ClC-1 protein. Emerging evidence indicates that the effects of some mutations may entail impaired ClC-1 protein homeostasis (proteostasis). Proteostasis of membrane proteins comprises of biogenesis at the endoplasmic reticulum (ER), trafficking to the surface membrane, and protein turn-over at the plasma membrane. Maintenance of proteostasis requires the coordination of a wide variety of different molecular chaperones and protein quality control factors. A number of regulatory molecules have recently been shown to contribute to post-translational modifications of ClC-1 and play critical roles in the ER quality control, membrane trafficking, and peripheral quality control of this Jeng et al.ClC-1 Proteostasis and Myotonia chloride channel. Further illumination of the mechanisms of ClC-1 proteostasis network will enhance our understanding of the molecular pathophysiology of myotonia congenita, and may also bring to light novel therapeutic targets for skeletal muscle dysfunction caused by myotonia and other pathological conditions.

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“…Proteins trafficking through the ER that fail to fold properly are usually degraded to prevent the accumulation of toxic aggregates. Most of these aberrantly folded polypeptides undergo retrotranslocation into the cytosol, poly-ubiquitination, and degradation by the 26S proteasome, a process known as ER-associated degradation (ERAD) 38,39,[63][64][65] . While ERAD is the main degradation pathway for most misfolded ER proteins, GPI-anchored proteins like PrP are primarily cleared by the so-called ER-to-lysosome-associated degradation pathway (ERLAD) [66][67][68] .…”

Section: Sm875 Induces the Degradation Of Prp By The Lysosomesmentioning

confidence: 99%

Pharmacological Protein Inactivation by Targeting Folding Intermediates

Spagnolli

Massignan

Astolfi

et al. 2020

Preprint

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Recent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. Using these techniques to study the negative regulation of the androgen receptor (AR), we discovered a key functional role played by non-native metastable states appearing along the folding pathway of this protein. This unexpected observation inspired us to design a completely novel drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein expression by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular prion protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases. We predicted the all-atom structure of an intermediate appearing along the folding pathway of PrP, and identified four different small molecule ligands for this conformer, all capable of selectively lowering the expression of the protein by promoting its degradation. Our data support the notion that the level of target proteins could be modulated by acting on their folding pathways, implying a previously unappreciated role for folding intermediates in the biological regulation of protein expression. INTRODUCTIONProtein expression and function in eukaryotic cells are tightly harmonized processes modulated by the combination of different layers of regulation. These may occur at the level of gene transcription, processing, stability, and translation of the mRNA as well as by assembly, post-translational modifications, sorting, recycling, and degradation of the corresponding polypeptide 1 . In addition, the expression of a small subset of proteins is known to be regulated by the presence of specific ligands, which are required along the folding pathway to reach the native, functional state 2-7 . For example, the folding of the kinase-inducible domain of the cAMP-response-element-binding protein is known to proceed only upon interaction with the CREB-binding protein 8 . Other typical examples of liganddependent folding mechanism include nuclear receptors, such as estrogen and androgen receptors 9 . The integration between these pathways and the protein quality control machinery, deputed to avoid the production and accumulation of aberrantly folded proteins, is known as proteostasis 1,10 . Mechanisms by which proteostasis is ensured include chaperone-assisted protein folding as well as re-routing and degradation of misfolded protein conformers. These processes play a fundamental role during development, aging, tolerance to environmental stresses, and minimize alterations of proteome homeostasis induced by pathogens 11 . Consistently, a large percentage of human pathologies are linked to alterations of proteostasis, including a broad spectrum of age-related brain disorders, known as neurodegenerative diseases, ...

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Protein quality control in the secretory pathway

Cited by 291 publications

References 243 publications

Translational Control of Secretory Proteins in Health and Disease

Translational Control of Secretory Proteins in Health and Disease

Defective Gating and Proteostasis of Human ClC-1 Chloride Channel: Molecular Pathophysiology of Myotonia Congenita

Pharmacological Protein Inactivation by Targeting Folding Intermediates

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