Co-chaperones of the Human Endoplasmic Reticulum: An Update

Melnyk, Armin; Lang, Sven; Sicking, Mark; Zimmermann, Richard; Jung, Martin

doi:10.1007/978-3-031-14740-1_9

Cited by 3 publications

(2 citation statements)

References 260 publications

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“… 71 , 72 , 73 The human ortholog of PfHSP70-2 is GRP78 which resides in the lumen of the ER, binds to newly formed polypeptides translocating through the ER Sec complex and assists folding into the native state. 74 , 75 During stress conditions, normal ER functions are disturbed leading to the accumulation of misfolded proteins, which triggers the onset of the unfolded protein response (UPR) pathway to restore normal ER functioning. The UPR, in turn, upregulates the expression of ER chaperones to degrade misfolded proteins.…”

Section: Malarial Hsps and Their Complexes As Drug Targetsmentioning

confidence: 99%

“… 79 GRP78 interacts with its partner ER-resident HSP40, Sec63, which is involved in protein translocation into the ER. 75 , 80 PfHSP70-2 has been found to regulate eIF2-α-mediated arrest of protein translation, an important event during the schizont and gametocyte stages. 77 , 81 , 82 , 83 PfHsp70-2 was reported to be involved in the oxidative folding of ER proteins in association with ER-resident folding catalysts, a PfHSP40 (Pfj2), and a protein disulfide isomerase (PfPDI-8).…”

Section: Malarial Hsps and Their Complexes As Drug Targetsmentioning

confidence: 99%

See 1 more Smart Citation

Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update

Ahmad,

Alhammadi,

Almaazmi

et al. 2024

Cell Stress and Chaperones

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Section: Malarial Hsps and Their Complexes As Drug Targetsmentioning

confidence: 99%

Section: Malarial Hsps and Their Complexes As Drug Targetsmentioning

confidence: 99%

Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update

Ahmad,

Alhammadi,

Almaazmi

et al. 2024

Cell Stress and Chaperones

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A functional chaperone condensate in the endoplasmic reticulum

Hiller,

Leder,

Mas

et al. 2024

Preprint

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One third of eukaryotic proteins are processed within the endoplasmic reticulum (ER) to obtain their correct structure1-3. This function is ensured by a network of molecular chaperones that recognizes client proteins and assists their folding4,5. How the ER chaperones organize in a supramolecular manner to exert their cooperativity has, however, remained unclear. Here, we report the discovery of a multi-chaperone condensate in the ER lumen, which is formed around the chaperone PDIA6 during protein folding homeostasis. We resolve the structure of PDIA6 and the mechanism underlying its condensate formation at the atomic and cellular level. We find that the multivalency required for PDIA6 phase separation is created by two specific interfaces. One of these interfaces is regulated by a Ca2+-dependent molecular switch, allowing dynamic adaptations to ER stress. The PDIA6 condensates recruit further chaperones, in particular Hsp70 BiP, J-domain protein ERdj3, disulfide isomerase PDIA1 and Hsp90 Grp94, which are the essential components of the early folding machinery. The chaperone condensates enhance folding of client proteins, which we show exemplarily on proinsulin, and prevent protein misfolding in the ER lumen. The PDIA6-scaffolded chaperone condensates hence provide the functional basis for spatial and temporal coordination of the dynamic ER chaperone network.

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The endoplasmic reticulum membrane protein Sec62 as potential therapeutic target in SEC62 overexpressing tumors

et al. 2022

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The human SEC62 gene is located on chromosome 3q, was characterized as a tumor driver gene and is found to be overexpressed in an ever-growing number of tumors, particularly those with 3q26 amplification. Where analyzed, SEC62 overexpression was associated with poor prognosis. Sec62 protein is a membrane protein of the endoplasmic reticulum (ER) and has functions in endoplasmic reticulum protein import, endoplasmic reticulum-phagy and -in cooperation with the cytosolic protein calmodulin- the maintenance of cellular calcium homeostasis. Various human tumors show SEC62 overexpression in immunohistochemistry and corresponding cell lines confirm this phenomenon in western blots and immunofluorescence. Furthermore, these tumor cells are characterized by increased stress tolerance and migratory as well as invasive potential, three hallmarks of cancer cells. Strikingly, plasmid-driven overexpression of SEC62 in non-SEC62 overexpressing cells introduces the same three hallmarks of cancer into the transfected cells. Depletion of Sec62 from either type of SEC62 overexpressing tumor cells by treatment with SEC62-targeting siRNAs leads to reduced stress tolerance and reduced migratory as well as invasive potential. Where tested, treatment of SEC62 overexpressing tumor cells with the small molecule/calmodulin antagonist trifluoperazine (TFP) phenocopied the effect of SEC62-targeting siRNAs. Recently, first phase II clinical trials with the prodrug mipsagargin/G202, which targets cellular calcium homeostasis in prostate cells as well as neovascular tissue in various tumors were started. According to experiments with tumor cell lines, however, SEC62 overexpressing tumor cells may be less responsive or resistant against such treatment. Therefore, murine tumor models for tumor growth or metastasis were evaluated with respect to their responsiveness to treatment with a mipsagargin analog (thapsigargin), or trifluoperazine, which had previously been in clinical use for the treatment of schizophrenia, or with the combination of both drugs. So far, no additive effect of the two drugs was observed but trifluoperazine had an inhibitory effect on tumor growth and metastatic potential in the models. Here, we review the state of affairs.

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Co-chaperones of the Human Endoplasmic Reticulum: An Update

Cited by 3 publications

References 260 publications

Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update

Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update

A functional chaperone condensate in the endoplasmic reticulum

The endoplasmic reticulum membrane protein Sec62 as potential therapeutic target in SEC62 overexpressing tumors

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