NF-κB activated by ER calcium release inhibits Aβ-mediated expression of CHOP protein: Enhancement by AD-linked mutant presenilin 1

To elucidate new functions of sphingosine (Sph), we demonstrate that the spontaneous elevation of intracellular Sph levels via caged Sph leads to a significant and transient calcium release from acidic stores that is independent of sphingosine 1-phosphate, extracellular and ER calcium levels. This photo-induced Sph-driven calcium release requires the two-pore channel 1 (TPC1) residing on endosomes and lysosomes. Further, uncaging of Sph leads to the translocation of the autophagy-relevant transcription factor EB (TFEB) to the nucleus specifically after lysosomal calcium release. We confirm that Sph accumulates in late endosomes and lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging. We conclude that sphingosine is a positive regulator of calcium release from acidic stores and that understanding the interplay between Sph homeostasis, calcium signaling and autophagy will be crucial in developing new therapies for lipid storage disorders such as NPC.

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Involvement of c-Fos in signaling grp78 induction following ER calcium release

Oncogene ◽

10.1038/sj.onc.1203994 ◽

2000 ◽

Vol 19 (51) ◽

pp. 5936-5943 ◽

Cited By ~ 16

Author(s):

Huiling He ◽

Karen McColl ◽

Clark W Distelhorst

Keyword(s):

Calcium Release ◽

Er Calcium

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Elevated ceramide is downstream of altered calcium homeostasis in low serum-induced apoptosis

AJP Cell Physiology ◽

10.1152/ajpcell.2000.279.5.c1640 ◽

2000 ◽

Vol 279 (5) ◽

pp. C1640-C1647 ◽

Cited By ~ 16

Author(s):

Supriya Jayadev ◽

J. Carl Barrett ◽

Elizabeth Murphy

Keyword(s):

Calcium Release ◽

Calcium Depletion ◽

Hamster Embryo Cells ◽

Embryo Cells ◽

Immortalized Cell ◽

Induced Apoptosis ◽

Ceramide Generation ◽

The Relationship ◽

Er Calcium ◽

Low Serum

Two immortalized cell lines, sup (+) and sup (−), derived from mutagenized Syrian hamster embryo cells, were used to study the relationship and temporal order between calcium and ceramide signals during apoptosis. The early preneoplastic cells, termed sup (+), suppress tumorigenicity when hybridized with tumor cells, whereas later-stage sup (−) cells do not. In reduced serum conditions, sup (+) cells cease proliferating and undergo apoptosis; in contrast, sup (−) cells continue slow growth and undergo necrosis. In sup (+) cells, decreased endoplasmic reticulum (ER) calcium occurs 4 h after low serum treatment and precedes apoptosis. Significant elevations in ceramide are observed 16 h after reduced serum treatment of sup (+) cells but are not found in sup (−) cells. Inhibiting ER calcium depletion in low serum-treated sup (+) cells by treating with high levels of calcium prevents both ceramide generation and apoptosis. Conversely, inducing ER calcium depletion in sup (−) cells by treating with low serum plus thapsigargin results in elevated ceramide levels and apoptosis. Furthermore, C6-ceramide treatment induced apoptosis of sup (−) cells in low serum, a condition that does not normally cause apoptosis. C6-ceramide treatment did not induce apoptosis in either sup (+) or sup (−) cells in 10% serum but did cause G2/M arrest. These studies show that ceramide production is downstream of ER calcium release.

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The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0907555106 ◽

2009 ◽

Vol 106 (34) ◽

pp. 14397-14402 ◽

Cited By ~ 184

Author(s):

Y.-P. Rong ◽

G. Bultynck ◽

A. S. Aromolaran ◽

F. Zhong ◽

J. B. Parys ◽

...

Keyword(s):

Calcium Release ◽

Ip3 Receptor ◽

Er Calcium

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Atf-6 regulates lifespan through ER-mitochondrial calcium homeostasis

10.1101/2020.01.14.906693 ◽

2020 ◽

Author(s):

Kristopher Burkewitz ◽

Sneha Dutta ◽

Charlotte A. Kelley ◽

Michael Steinbaugh ◽

Erin J. Cram ◽

...

Keyword(s):

Calcium Homeostasis ◽

Calcium Release ◽

Calcium Handling ◽

Mitochondrial Calcium ◽

Calcium Release Channel ◽

Direct Role ◽

Release Channel ◽

Long Life ◽

Organelle Communication ◽

Er Calcium

AbstractFunctional crosstalk between organelles is critical for maintaining cellular homeostasis. Individually, dysfunction of both endoplasmic reticulum (ER) and mitochondria have been linked to cellular and organismal aging, but little is known about how mechanisms of inter-organelle communication might be targeted to extended longevity. The metazoan unfolded protein response (UPR) maintains ER health through a variety of mechanisms beyond its canonical role in proteostasis, including calcium storage and lipid metabolism. Here we provide evidence that in C. elegans, inhibition of the conserved UPR mediator, activating transcription factor (atf)-6 increases lifespan via modulation of calcium homeostasis and signaling to the mitochondria. Loss of atf-6 confers long life via downregulation of the ER calcium buffering protein, calreticulin. Function of the ER calcium release channel, the inositol triphosphate receptor (IP3R/itr-1), is required for atf-6 mutant longevity while a gain-of-function IP3R/itr-1 mutation is sufficient to extend lifespan. IP3R dysfunction leads to altered mitochondrial behavior and hyperfused morphology, which is sufficient to suppress long life in atf-6 mutants. Highlighting a novel and direct role for this inter-organelle coordination of calcium in longevity, the mitochondrial calcium import channel, mcu-1, is also required for atf-6 mutant longevity. Altogether this study reveals the importance of organellar coordination of calcium handling in determining the quality of aging, and highlights calcium homeostasis as a critical output for the UPR and atf-6 in particular.

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Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes

10.1101/2020.11.03.366484 ◽

2020 ◽

Author(s):

Steffen Preissler ◽

Claudia Rato ◽

Yahui Yan ◽

Luke A. Perera ◽

Aron Czako ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Calcium Release ◽

Atp Hydrolysis ◽

Secretory Cells ◽

Nucleotide Exchange ◽

Calcium Depletion ◽

Er Quality Control ◽

Cellular Processes ◽

The Unfolded Protein Response ◽

Er Calcium

AbstractThe metazoan endoplasmic reticulum (ER) serves both as a hub for maturation of secreted proteins and as an intracellular calcium storage compartment, facilitating calcium release-dependent cellular processes. ER calcium depletion robustly activates the unfolded protein response (UPR). However, it is unclear how fluctuations in ER calcium impact organellar proteostasis. Here we report that calcium selectively affects the dynamics of the abundant metazoan ER Hsp70 chaperone BiP, by enhancing its affinity for ADP. In the calcium replete ER, ADP rebinding to post-ATP hydrolysis BiP-substrate complexes competes with ATP binding during both spontaneous and co-chaperone-assisted nucleotide exchange, favouring substrate retention. Conversely, in the calcium depleted ER, relative acceleration of ADP-to-ATP exchange favours substrate release. These findings explain the rapid dissociation of certain substrates from BiP observed in the calcium-depleted ER and suggest a mechanism for tuning ER quality control and coupling UPR activity to signals that mobilise ER calcium in secretory cells.

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