Endoplasmic Reticulum Proteostasis Influences the Oligomeric State of an Amyloidogenic Protein Secreted from Mammalian Cells

Chen, John J.; Genereux, Joseph C.; Suh, Eul Hyun; Vartabedian, Vincent F.; Rius, Bibiana; Qu, Song; Dendle, Maria T. A.; Wiseman, R. Luke

doi:10.1016/j.chembiol.2016.09.001

Cited by 33 publications

(58 citation statements)

References 27 publications

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“…ERdj3 binds to FT TTR A25T in the ER and extracellular environments (Shoulders et al , ; Genereux et al , ). In addition, FT TTR A25T secretory proteostasis is highly sensitive to ER stress (Chen et al , ). Tg‐induced ER stress decreases secretion of total FT TTR A25T (Shoulders et al , ) and increases the extracellular population of FT TTR A25T that accumulates as soluble aggregates commonly associated with human disease (Chen et al , ).…”

Section: Resultsmentioning

confidence: 99%

The endoplasmic reticulum HSP40 co‐chaperone ERdj3/DNAJB11 assembles and functions as a tetramer

Chen

Chowdhury

et al. 2017

The EMBO Journal

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ERdj3/DNAJB11 is an endoplasmic reticulum (ER)-targeted HSP40 co-chaperone that performs multifaceted functions involved in coordinating ER and extracellular proteostasis. Here, we show that ERdj3 assembles into a native tetramer that is distinct from the dimeric structure observed for other HSP40 co-chaperones. An electron microscopy structural model of full-length ERdj3 shows that these tetramers are arranged as a dimer of dimers formed by distinct inter-subunit interactions involving ERdj3 domain II and domain III Targeted deletion of residues 175-190 within domain II renders ERdj3 a stable dimer that is folded and efficiently secreted from mammalian cells. This dimeric ERdj3 shows impaired substrate binding both in the ER and extracellular environments and reduced interactions with the ER HSP70 chaperone BiP. Furthermore, we show that overexpression of dimeric ERdj3 exacerbates ER stress-dependent reductions in the secretion of a destabilized, aggregation-prone protein and increases its accumulation as soluble oligomers in extracellular environments. These results reveal ERdj3 tetramerization as an important structural framework for ERdj3 functions involved in coordinating ER and extracellular proteostasis in the presence and absence of ER stress.

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Section: Resultsmentioning

confidence: 99%

The endoplasmic reticulum HSP40 co‐chaperone ERdj3/DNAJB11 assembles and functions as a tetramer

Chen

Chowdhury

et al. 2017

The EMBO Journal

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“…For example, ER stress increases secretion of destabilized TTR variants in non-native conformations that accumulate in the extracellular space as soluble oligomers commonly associated with proteotoxicity [33]. Similarly, ER stress increases the trafficking of destabilized variants of the GPI-anchored prion protein or the integral membrane protein ABCA1 to the plasma membrane in misfolded, non-functional conformations [34–36].…”

Section: Disruptions In Er Quality Control Are a Threat To Secretory mentioning

confidence: 99%

“…This cell line facilitated the characterization of transcriptional reprogramming of ER proteostasis pathways by the two UPR arms separately and synergistically [17]. Furthermore, these tools have defined the distinct roles for IRE1/XBP1s or ATF6 in regulating ER secretory proteostasis for a number of proteins that aggregate in association with diverse protein aggregation diseases [17, 33, 39, 43]. …”

Section: Impacting Er Quality Control Of Disease-associated Protein Tmentioning

confidence: 99%

“…This has been best demonstrated by evaluating how UPR signaling pathways influence the partitioning of destabilized, disease-associated proteins between folding/trafficking or degradation pathways within the ER. For example, stress-independent activation of ATF6, but not XBP1s, selectively reduces secretion of destabilized, aggregation prone variants of TTR (Table 1) [17, 33]. This reduced secretion corresponds with increased targeting of these variants to degradation through mechanisms such as ERAD and autophagy.…”

Section: Impacting Er Quality Control Of Disease-associated Protein Tmentioning

confidence: 99%

“…Despite this capacity for IRE1/XBP1s or ATF6 activation to influence ER quality control for destabilized proteins, the secretion of wild-type or stable non-amyloidogenic variants of TTR, LC, rhodopsin or A1AT is not significantly reduced by stress-independent IRE1/XBP1s and/or ATF6 activation [17, 33, 39–42]. Similarly, secretion of endogenous secretory proteome does not appear to be significantly impacted by activation of these UPR-associated transcription factors [17].…”

Section: Impacting Er Quality Control Of Disease-associated Protein Tmentioning

confidence: 99%

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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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The Transthyretin Protein and Amyloidosis – an Extraordinary Chemical Biology Platform

Hammarström

2024

Israel Journal of Chemistry

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The amyloidoses are diseases caused by accumulation of amyloid fibrils from over 40 different human misfolded proteins in various organs of the body depending on precursor protein. Amyloidogenesis is a self‐perpetuating reaction with deleterious consequences causing degeneration in cells and organs where depositions occur. Transthyretin, TTR, is an amyloidogenic protein causing sporadic disease from the wild‐type protein during aging and from numerous different autosomal dominant familial mutations at earlier ages depending on the sequence of the hereditary variant. Until recently the disease process was poorly understood, and therapies were scarce. Over the past decades, spurred by clinical data, using chemical biology research, the mechanisms of TTR production and misfolding have been elucidated affording almost complete coverage of the TTR amyloidogenesis pathway to be targeted. This translational science success has provided a plethora of therapeutic options for the TTR amyloidoses providing an inspiring example for success in previously intractable diseases.

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Endoplasmic Reticulum Proteostasis Influences the Oligomeric State of an Amyloidogenic Protein Secreted from Mammalian Cells

Cited by 33 publications

References 27 publications

The endoplasmic reticulum HSP40 co‐chaperone ERdj3/DNAJB11 assembles and functions as a tetramer

The endoplasmic reticulum HSP40 co‐chaperone ERdj3/DNAJB11 assembles and functions as a tetramer

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

The Transthyretin Protein and Amyloidosis – an Extraordinary Chemical Biology Platform

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