New tricks for KDEL receptors

Li, Ming Yuan; Bruzzone, Roberto; Wang, Peigang

doi:10.18632/oncotarget.5444

Cited by 4 publications

(5 citation statements)

References 8 publications

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“…Retro-transport of these chaperones encourages the retrieval and return of misfolded proteins to the ER for refolding or ER-associated degradation, thus regulating ER quality (Smith et al, 2011). However, the extensively sustained induction of ER chaperones and cargo loading may saturate KDELR-mediated retrieval and modify the expression and distribution of the KDELR (Li et al, 2015). When KDELR-mediated retrieval is limited, a number of newly synthesized ER-retained chaperones, such as the heat shock protein family including GRP78, GRP94 and other co-chaperones like folding enzymes PDI, may avoid retrieval and exit the ER lumen, dramatically aggravating ER stress (Ni and Lee, 2007).…”

Section: Discussionmentioning

confidence: 99%

Santacruzamate A Ameliorates AD-Like Pathology by Enhancing ER Stress Tolerance Through Regulating the Functions of KDELR and Mia40-ALR in vivo and in vitro

Chen

Liu

Tan

et al. 2019

Front. Cell. Neurosci.

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Aggregated amyloid-β protein (Aβ) and Aβ-induced neuronal apoptosis have been implicated as critical factors in the pathophysiology of Alzheimer’s disease (AD). Certain preclinical results have indicated that the increased accumulation of protein aggregates in AD-affected neurons activates the unfolded protein response (UPR), a pathological phenomenon, which predominantly mediates the aberrant endoplasmic reticulum (ER) stress and apoptotic cascades in neuronal cells. In the present study, we confirmed that Santacruzamate A (STA, a natural product isolated from a Panamanian marine cyanobacterium) attenuates Aβ protein fragment 25–35 (Aβ 25–35 )-induced toxicity in PC12 cells and rescues cognitive deficits in APPswe/PS1dE9 mice by enhancing ER stress tolerance. We first demonstrated the anti-apoptotic effects of STA by evaluating caspase-3 activity, annexin V/propidium iodide (PI) staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Behavioral testing of STA-treated APPswe/PS1dE9 mice showed that the pronounced memory impairments were ameliorated and that the consolidated memories were stably maintained over a 2-week period. The mechanistic studies provided evidence that STA inhibited Aβ 25–35 -induced UPR and ER stress by regulating the ER retention signal (KDEL) receptor, which reinforced the retention of resident chaperones in the ER lumen. Furthermore, STA regulated the expression of the mitochondrial intermembrane space assembly protein 40 (Mia40) and augmenter of liver regeneration (ALR), which ultimately attenuated the mitochondrial fission and apoptosis pathways. Together, our present findings suggest that the KDEL receptor and Mia40-ALR play a role in mitigating Aβ 25–35 -induced neurotoxicity, which might in turn positively regulate learning and memory. These observations support that STA may be a promising agent for reversing the progression of AD.

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Section: Discussionmentioning

confidence: 99%

Santacruzamate A Ameliorates AD-Like Pathology by Enhancing ER Stress Tolerance Through Regulating the Functions of KDELR and Mia40-ALR in vivo and in vitro

Chen

Liu

Tan

et al. 2019

Front. Cell. Neurosci.

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“…Recently, Li et al [ 19 ] reported that dengue virus prM protein interacted with the KDEL receptor in the ER. They further demonstrated that blocking the host KDELR retrieval system led to reducing the viral particles’ release, indicating that KDELR protein is an intracellular viral receptor assisting in DENV exit from the ER [ 20 ]. We noticed that enteroviral infections could reorganize the cellular secretory pathway, including the generation of PI4P lipid-enriched replication organelles; the PI4P lipid-rich membrane led to facilitated viral RNA replication, instead of using the conventional secretory pathway for the intracellular trafficking of viral particles [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

A KDEL Retrieval System for ER-Golgi Transport of Japanese Encephalitis Viral Particles

Wang

Chen

et al. 2016

Viruses

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Evidence has emerged that RNA viruses utilize the host secretory pathway for processing and trafficking mature viral particles and for exiting the infected cells. Upon completing the complex assembly process, the viral particles take advantage of the cellular secretory trafficking machinery for their intracellular trafficking toward the Golgi organelle and budding or export of virions. In this study, we showed that Japanese encephalitis virus (JEV)-induced extracellular GRP78 contains no KDEL motif using an anti-KDEL-specific antibody. Overexpression of the KDEL-truncated GRP78 in the GPR78 knocked down cells significantly reduced JEV infectivity, suggesting that the KDEL motif is required for GRP78 function in the release of JE viral particles. In addition, we demonstrated the KDELR protein, an ER-Golgi retrieval system component, is associated with viral envelope proteins and is engaged in the subcellular localization of viral particles in Golgi. More importantly, accumulation of intracellular virions was observed in the KDELR knocked down cells, indicating that the KDELR protein mediated the intracellular trafficking of JE viral particles. Altogether, we demonstrated that intracellular trafficking of JE assembled viral particles was mediated by the host ER-Golgi retrieval system prior to exit by the secretory pathway.

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“…In addition, a furin cleave site was also incorporated to allow the release of the accessory N‐terminal region in the endosome and the intracellular activity of ricin in a quasi‐native sequence format. A KDEL motif was also incorporated to favor endosomal escape . The plasmid construct pET22b‐T22‐mRTA‐H6, encoding the protein under the control of the bacteriophage T7 promoter, was generated by GeneArt and transformed into E. coli Origami B cells.…”

Section: Methodsmentioning

confidence: 99%

Selective CXCR4⁺ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin

Díaz

Pallarès

Cano‐Garrido

et al. 2018

Small

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Under the unmet need of efficient tumor-targeting drugs for oncology, a recombinant version of the plant toxin ricin (the modular protein T22-mRTA-H6) is engineered to self-assemble as protein-only, CXCR4-targeted nanoparticles. The soluble version of the construct self-organizes as regular 11 nm planar entities that are highly cytotoxic in cultured CXCR4 cancer cells upon short time exposure, with a determined IC50 in the nanomolar order of magnitude. The chemical inhibition of CXCR4 binding sites in exposed cells results in a dramatic reduction of the cytotoxic potency, proving the receptor-dependent mechanism of cytotoxicity. The insoluble version of T22-mRTA-H6 is, contrarily, moderately active, indicating that free, nanostructured protein is the optimal drug form. In animal models of acute myeloid leukemia, T22-mRTA-H6 nanoparticles show an impressive and highly selective therapeutic effect, dramatically reducing the leukemia cells affectation of clinically relevant organs. Functionalized T22-mRTA-H6 nanoparticles are then promising prototypes of chemically homogeneous, highly potent antitumor nanostructured toxins for precise oncotherapies based on self-mediated intracellular drug delivery.

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New tricks for KDEL receptors

Cited by 4 publications

References 8 publications

Santacruzamate A Ameliorates AD-Like Pathology by Enhancing ER Stress Tolerance Through Regulating the Functions of KDELR and Mia40-ALR in vivo and in vitro

Santacruzamate A Ameliorates AD-Like Pathology by Enhancing ER Stress Tolerance Through Regulating the Functions of KDELR and Mia40-ALR in vivo and in vitro

A KDEL Retrieval System for ER-Golgi Transport of Japanese Encephalitis Viral Particles

Selective CXCR4⁺ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin

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New tricks for KDEL receptors

Cited by 4 publications

References 8 publications

Santacruzamate A Ameliorates AD-Like Pathology by Enhancing ER Stress Tolerance Through Regulating the Functions of KDELR and Mia40-ALR in vivo and in vitro

Santacruzamate A Ameliorates AD-Like Pathology by Enhancing ER Stress Tolerance Through Regulating the Functions of KDELR and Mia40-ALR in vivo and in vitro

A KDEL Retrieval System for ER-Golgi Transport of Japanese Encephalitis Viral Particles

Selective CXCR4+ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin

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Product

Resources

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Selective CXCR4⁺ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin