Nuclear localisation of calreticulin in vivo is enhanced by its interaction with glucocorticoid receptors

AbstractThe multi-functional protein calreticulin (CRT) is normally found within the lumen of the endoplasmic reticulum (ER). However, some of its proposed functions require it to be located within the nucleus, where its presence is contentious. We have investigated this in live COS7, HeLa and LM(TK−) cells using green fluorescent protein (GFP)-fusion proteins. GFP-CRT, and GFP, with an ER signal peptide and a KDEL sequence (ER-GFP), were localised to the ER. In addition, GFP-CRT was located in the nucleus of all the cell types at low levels. The higher levels of nuclear fluorescence in LM(TK−) and HeLa cells suggested that glucocorticoid receptors might enhance nuclear localisation of calreticulin. Dexamethasone treatment of LM(TK−) cells doubled the amount of nuclear GFP-CRT, but did not affect the localisation of a GFP-CRT fusion in which the glucocorticoid receptor-binding N-domain of calreticulin had been deleted. Thus, despite ER targeting and retention signals, calreticulin is also located within the nucleus where its presence increases due to its interaction with glucocorticoid receptors.© 1997 Federation of European Biochemical Societies

Calcium-induced calcium release

status: publishe

Redoxing calcium from the ER

Inositol 1,4,5-trisphosphate (InsP3)-induced calcium release from the endoplasmic reticulum (ER) intracellular calcium store regulates cellular functions from the beginning of life at fertilization until death. In this issue of Cell, Mikoshiba and colleagues describe a novel mode of regulation of the InsP3 receptor (InsP3R) governed by ER luminal redox status, calcium, and pH (Higo et al., 2005)

Calcium influx: is Homer the missing link?

AbstractCalcium signals in cells can arise via release from intracellular stores or influx across the plasma membrane. Recent studies have shed new light on the multi-protein signalling complexes that mediate communication between calcium stores and plasma membrane calcium channels

Cell signalling: IP₃ receptors channel calcium into cell death

There is substantial evidence that Ca2+ fluxes occur during most forms of apoptosis, and that inhibiting such fluxes protects cells from death. IP3 receptors – ligand-gated channels that release Ca2+ from intracellular stores – are emerging as key sites for regulation by pro- and anti-apoptotic factors

Glucocorticoid-mediated Inhibition of Lck Modulates the Pattern of T Cell Receptor-induced Calcium Signals by Down-regulating Inositol 1,4,5-Trisphosphate Receptors

Glucocorticoids are potent immunosuppressive agents that block upstream signaling events required for T cell receptor (TCR) activation. However, the mechanism by which glucocorticoids inhibit downstream responses, such as inositol 1,4,5-trisphosphate (IP3)-induced calcium signals, is not completely understood. Here we demonstrate that low concentrations of dexamethasone rapidly convert transient calcium elevations to oscillations after strong TCR stimulation. Dexamethasone converted the pattern of calcium signaling by inhibiting the Src family kinase Lck, which was shown to interact with and positively regulate Type I IP3 receptor. In addition, low concentrations of dexamethasone were sufficient to inhibit calcium oscillations and interleukin-2 mRNA after weak TCR stimulation. Together, these findings indicate that by inhibiting Lck and subsequently down-regulating IP3 receptors, glucocorticoids suppress immune responses by weakening the strength of the TCR signal