KDEL Receptor 1 Contributes to Cell Surface Association of Protein Disulfide Isomerases

Bartels, Anne-Kathrin; Göttert, Sascha; Desel, Christine; Schäfer, Miriam R.; Krossa, Sebastian; Scheidig, Axel J.; Grötzinger, Joachim; Lorenzen, Inken

doi:10.33594/000000059

Cited by 12 publications

(9 citation statements)

References 66 publications

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“…Given their role in trafficking and autophagy, KDEL receptors may also promote the degradation and removal of misfolded proteins during ER stress. KDEL receptors traffic to the cell surface basally and under stress conditions, where they can interact with ERS ligands to form clusters and potentially promote signaling [ 21 , 23 , 24 , 94 , 95 ]. The presence of KDEL receptors at the cell surface may function to retrieve secreted ERS proteins from the extracellular space.…”

Section: Discussionmentioning

confidence: 99%

“…Cell surface KDEL receptors have been postulated as a putative receptor for extracellular CDNF, suggesting that KDEL receptors adaptively re-distribute in response to changes to the ER microenvironment [ 22 ]. Moreover, KDEL receptors have been implicated in the trafficking of ERS proteins to the cell surface [ 23 ]. Interestingly, cell-surface clustering of KDEL receptors is dependent on cargo, dose, and temperature [ 24 ].…”

Section: Kdel Retrieval Pathway and Kdel Receptorsmentioning

confidence: 99%

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The Function of KDEL Receptors as UPR Genes in Disease

Wires

Kennedy

Harvey

2021

IJMS

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The KDEL receptor retrieval pathway is essential for maintaining resident proteins in the endoplasmic reticulum (ER) lumen. ER resident proteins serve a variety of functions, including protein folding and maturation. Perturbations to the lumenal ER microenvironment, such as calcium depletion, can cause protein misfolding and activation of the unfolded protein response (UPR). Additionally, ER resident proteins are secreted from the cell by overwhelming the KDEL receptor retrieval pathway. Recent data show that KDEL receptors are also activated during the UPR through the IRE1/XBP1 signaling pathway as an adaptive response to cellular stress set forth to reduce the loss of ER resident proteins. This review will discuss the emerging connection between UPR activation and KDEL receptors as it pertains to ER proteostasis and disease states.

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Section: Discussionmentioning

confidence: 99%

Section: Kdel Retrieval Pathway and Kdel Receptorsmentioning

confidence: 99%

The Function of KDEL Receptors as UPR Genes in Disease

Wires

Kennedy

Harvey

2021

IJMS

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“…More recently, Bartels et al proposed that PDI, ERp57 and ERp5 remain on the surface of HEK293 cells through their binding to the KDEL receptor 1 (KDELR1) (Bartels et al, 2019). Nonetheless, because the canonical functions of KDELR1 are retrograde transport of its ligands from Golgi to the ER, how PDI selectively engages with KDELR1 and together translocate to the cell surface remain elusive.…”

Section: Cells Referencementioning

confidence: 99%

“…Secondly, it is also possible that modulation of the COPII-dependent sorting machinery could saturate the KDEL retrieval system, thus leading to the secretion of KDEL-bearing proteins such as PDI (Ma et al, 2017). Thirdly, because KDELR1 can translocate to the cell surface, it could also facilitate the cell surface retention of PDI and other thiol isomerases including ERp57 and ERp5 (Bartels et al, 2019;Wan et al, 2012).…”

Section: Cells Referencementioning

confidence: 99%

Pathophysiological roles of cell surface and extracellular protein disulfide isomerase and their molecular mechanisms

Chiu

Chen

et al. 2021

British J Pharmacology

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Protein disulfide isomerase (PDI) is the prototypic member of the thiol isomerase family that catalyses disulfide bond rearrangement. Initially identified in the endoplasmic reticulum as folding catalysts, PDI and other members in its family have also been widely reported to reside on the cell surface and in the extracellular matrix. Although how PDI is exported and retained on the cell surface remains a subject of debate, this unique pool of PDI is developing into an important mechanism underlying the redox regulation of protein sulfhydryls that are critical for the cellular activities under various disease conditions. This review aims to provide an overview of the pathophysiological roles of surface and extracellular PDI and their underlying molecular mechanisms.Understanding the involvement of extracellular PDI in these diseases will advance our knowledge in the molecular aetiology to facilitate the development of novel pharmacological strategies by specifically targeting PDI in extracellular compartments.

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“…Notably, within the ER module, M83, there was increased abundance of chaperones (e.g. HSPA5, PDIA3, PDIA4, PDIA6, and DNAJC3) that are commonly engaged in presence of misfolded proteins (Bartels et al, 2019; Kim et al, 2020; Montibeller and de Belleroche, 2018; Synofzik et al, 2014; Wang et al, 2016). This elevation of ER stress modulators can be indicative of neurodegenerative states, in which the unfolded protein response (UPR) is activated to resolve misfolded species (Garcia-Huerta et al, 2016; Hetz and Saxena, 2017).…”

Section: Resultsmentioning

confidence: 99%

Genetic Disruption of WASHC4 Drives Endo-lysosomal Dysfunction and Cognitive-Movement Impairments in Mice and Humans

Courtland

Bradshaw

Waitt

et al. 2020

Preprint

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Mutation of the WASH complex subunit, SWIP, is implicated in human intellectual disability, but the cellular etiology of this association is unknown. We identify the neuronal WASH complex proteome, revealing a network of endosomal proteins. To uncover how dysfunction of endosomal SWIP leads to disease, we generate a mouse model of the human WASHC4c.3056C>G mutation. Quantitative spatial proteomics analysis of SWIPP1019R mouse brain reveals that this mutation destabilizes the WASH complex and uncovers significant perturbations in both endosomal and lysosomal pathways. Cellular and histological analyses confirm that SWIPP1019R results in endo-lysosomal disruption and uncover indicators of neurodegeneration. We find that SWIPP1019R not only impacts cognition, but also causes significant progressive motor deficits in mice. Remarkably, a retrospective analysis of SWIPP1019R patients confirms motor deficits in humans. Combined, these findings support the model that WASH complex destabilization, resulting from SWIPP1019R, drives cognitive and motor impairments via endo-lysosomal dysfunction in the brain.

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KDEL Receptor 1 Contributes to Cell Surface Association of Protein Disulfide Isomerases

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 12 publications

References 66 publications

The Function of KDEL Receptors as UPR Genes in Disease

The Function of KDEL Receptors as UPR Genes in Disease

Pathophysiological roles of cell surface and extracellular protein disulfide isomerase and their molecular mechanisms

Genetic Disruption of WASHC4 Drives Endo-lysosomal Dysfunction and Cognitive-Movement Impairments in Mice and Humans

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