Protein quality control at the endoplasmic reticulum

McCaffrey, Kathleen; Braakman, Ineke

doi:10.1042/ebc20160003

Cited by 129 publications

(157 citation statements)

References 28 publications

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“…Secretory proteome integrity (also referred to as secretory proteostasis) is primarily maintained by biologic pathways localized within the ER through a process termed ER quality control [1–3]. ER quality control functions to regulate the integrity of secreted proteins by partitioning non-native protein conformations between biologic pathways involved in ER protein folding or degradation (Fig.…”

Section: Secretory Proteostasis Is Regulated By the Unfolded Protein mentioning

confidence: 99%

Regulating Secretory Proteostasis through the Unfolded Protein Response: From Function to Therapy

Plate

Wiseman

2017

Trends in Cell Biology

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SUMMARY Imbalances in secretory proteostasis induced by genetic, environmental or aging related insults are pathologically associated with etiologically diverse protein misfolding diseases. To protect the secretory proteome from these insults, organisms evolved stress-responsive signaling pathways that regulate the composition and activity of biologic pathways involved in secretory proteostasis maintenance. The most prominent of these is the endoplasmic reticulum (ER) Unfolded Protein Response (UPR), which functions to regulate ER proteostasis in response to ER stress. While the signaling mechanisms involved in UPR activation are well-defined, the impact of UPR activation on secretory proteostasis is only becoming clear. Here, we highlight recent reports defining how activation of select UPR signaling pathways influences proteostasis within the ER and downstream secretory environments. Furthermore, we describe recent evidence that highlights the therapeutic potential for targeting UPR signaling pathways to correct pathologic disruption in secretory proteostasis associated with diverse types of protein misfolding diseases.

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Section: Secretory Proteostasis Is Regulated By the Unfolded Protein mentioning

confidence: 99%

Regulating Secretory Proteostasis through the Unfolded Protein Response: From Function to Therapy

Plate

Wiseman

2017

Trends in Cell Biology

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“…ER homeostasis can be perturbed when the folding capacity of the ER is saturated by expression of misfolded/unfolded proteins, activating the unfolded protein response (UPR). The UPR aims to alleviate the stress by reducing protein synthesis, increasing protein folding capacity by inducing ER chaperones, including PDI, or alternatively, by inducing ER-associated degradation (ERAD; Lee et al, 2010; McCaffrey and Braakman, 2016). …”

Section: Protein Quality Control Mechanismsmentioning

confidence: 99%

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

Shahheydari

Ragagnin

Walker

et al. 2017

Front. Mol. Neurosci.

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Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are now recognized to overlap clinically and pathologically, forming a continuous disease spectrum. In this review article, we detail the evidence for dysregulation of protein quality control mechanisms across the whole ALS-FTD continuum, by discussing the major proteins implicated in ALS and/or FTD. We also discuss possible ways in which protein quality mechanisms could be targeted therapeutically in these disorders and highlight promising protein quality control-based therapeutics for clinical trials.

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“…The ER is an elaborate membrane system that houses a variety of cellular functions that are critical for the maintenance of cellular homeostasis; synthesis of membrane-associated, luminal, and secreted proteins; correct folding and posttranslational modification of proteins and glycoproteins; lipid and steroid synthesis; and Ca 2+ signaling and storage (9)(10)(11). To perform these diverse functions, the ER engages a wide assortment of multifunctional integral membrane and luminal chaperones, including calnexin, an ER integral membrane protein (12).…”

Section: Introductionmentioning

confidence: 99%