Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation

Lioudyno, Maria; Kozak, J. Ashot; Penna, Aubin; Safrina, Olga; Zhang, Shenyuan L.; Sen, Debasish; Roos, Jack; Stauderman, Kenneth A.; Cahalan, Michael D.

doi:10.1073/pnas.0706122105

Cited by 235 publications

(254 citation statements)

References 35 publications

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“…A recent study examined the localization of STIM1 and Orai1 T-cell activated by contact with dendritic cells pulsed with enterotoxin. The authors reported that STIM1, Orai1, and the TCR all colocalized at the IS (Lioudyno et al, 2008). Our results in T-cells activated by super antigen-pulsed B-cells are consistent with their results in that we observed STIM1 and Orai1 accumulation at the contact surface that often overlapped with phosphotyrosine immunostaining marking the IS.…”

Section: Discussionsupporting

confidence: 82%

“…Cap formation appears to be a normal consequence of TCR activation because it does not depend on overexpression of either STIM1 or Orai1 and occurs in nontransformed PBLs as well as CD4 ϩ mouse T-cells. A recent epifluorescence study described only an accumulation of STIM1 and Orai1 at the IS between T lymphocytes and dendritic cells (Lioudyno et al, 2008). However, we were able to demonstrate caps in a variety of activated cells including mouse CD4 ϩ T-cells, human PBLs, and Jurkat cells.…”

Section: Discussionmentioning

confidence: 58%

“…Usually, they were seen near the contact surface between the two cells at the IS, often in clusters, and in a dense cap on the distal side of the T-cell away from the B-cell contact surface ( Figure 8A, Movie 7). There were also cells that showed an accumulation of STIM1 and Orai1 at the IS without caps (Supplemental Figure 8A), as there were in T-cells activated by contact with dendritic cells (Lioudyno et al, 2008). If no superantigen was present, there was no relocalization of Stim-CFP or Orai1-YFP (Supplemental Figure 8B).…”

Section: Dynamic Caps Form After Interactions Between Jurkat T-cellsmentioning

confidence: 99%

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Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

Barr

Bernot

Srikanth

et al. 2008

MBoC

129

142

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The proteins STIM1 and Orai1 are the long sought components of the store-operated channels required in T-cell activation. However, little is known about the interaction of these proteins in T-cells after engagement of the T-cell receptor. We found that T-cell receptor engagement caused STIM1 and Orai1 to colocalize in puncta near the site of stimulation and accumulate in a dense structure on the opposite side of the T-cell. FRET measurements showed a close interaction between STIM1 and Orai1 both in the puncta and in the dense cap-like structure. The formation of cap-like structures did not entail rearrangement of the entire endoplasmic reticulum. Cap formation depended on TCR engagement and tyrosine phosphorylation, but not on channel activity or Ca 2؉ influx. These caps were very dynamic in T-cells activated by contact with superantigen pulsed B-cells and could move from the distal pole to an existing or a newly forming immunological synapse. One function of this cap may be to provide preassembled Ca 2؉ channel components to existing and newly forming immunological synapses. INTRODUCTIONT-cell activation in response to antigen induces and requires the elevation of intracellular Ca 2ϩ (Hogan et al., 2003;Quintana et al., 2005;Feske, 2007). T-cell receptor (TCR) engagement leads to activation of well-documented signal transduction pathways that cause a rapid release of Ca 2ϩ from the endoplasmic reticulum (ER; Samelson, 2002;Panyi et al., 2004;Gwack et al., 2007a). The depletion of Ca 2ϩ from this internal store then leads to the opening of ion channels in the plasma membrane (PM) allowing an influx of Ca 2ϩ from outside the cell. The store-operated channel responsible for Ca 2ϩ influx in T-cells is known as the Ca 2ϩ release-activated Ca 2ϩ (CRAC) channel, which has been studied by electrophysiological techniques for many years (Lewis, 2001;Prakriya and Lewis, 2003;Cahalan et al., 2007;Hewavitharana et al., 2007;Hogan and Rao, 2007;Putney, 2007a).Sustained elevation of cytosolic Ca 2ϩ is required for complete T-cell activation (Iezzi et al., 1998;Lewis, 2001;Hogan et al., 2003;Feske, 2007). High levels of intracellular Ca 2ϩ are necessary to maintain the interaction between a T-cell and antigen-presenting cell (APC) that leads to formation of the specialized contact surface known as the immunological synapse (IS). Increased Ca 2ϩ levels are also required for the activation of transcription factors. In particular, elevated Ca 2ϩ maintains prolonged nuclear accumulation of nuclear factor of activated T-cells (NFAT) by activating the phosphatase calcineurin that dephosphorylates NFAT, allowing it to translocate to the nucleus and activate genes such as IL2 (Hogan et al., 2003;Macian, 2005). Several hours of Ca 2ϩ influx are required to complete the T-cell activation program, which involves expression of a large number of activation-associated genes (Lewis, 2001;Macian et al., 2002;Hogan et al., 2003).Although sustained Ca 2ϩ influx in T-cells has been studied for decades, the proteins involved have only been ident...

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 58%

Section: Dynamic Caps Form After Interactions Between Jurkat T-cellsmentioning

confidence: 99%

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Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

Barr

Bernot

Srikanth

et al. 2008

MBoC

129

142

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“…A particularly interesting example occurs during immune synapse formation between T cells and antigen-presenting cells (APCs), in which the T cell receptors engage peptide-MHC complexes on the APC. Shortly after cell -cell contact, STIM1 and Orai1 change their localization, accumulating initially at the synapse and then appearing to move in tandem to the distal end of the cell (Barr et al 2008;Lioudyno et al 2008). Ca 2þ imaging shows a domain of elevated [Ca 2þ ] i at the synapse, where it could potentially affect synapse stability, cytoskeletal remodeling, secretion, and other Ca 2þ -dependent events (Lioudyno et al 2008).…”

Section: Regulation Of Soce In a Physiological Contextmentioning

confidence: 99%

Store-Operated Calcium Channels: New Perspectives on Mechanism and Function

Lewis¹

2011

Cold Spring Harbor Perspectives in Biology

178

201

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Store-operated calcium channels (SOCs) are a nearly ubiquitous Ca 2þ entry pathway stimulated by numerous cell surface receptors via the reduction of Ca 2þ concentration in the ER. The discovery of STIM proteins as ER Ca 2þ sensors and Orai proteins as structural components of the Ca 2þ release-activated Ca 2þ (CRAC) channel, a prototypic SOC, opened the floodgates for exploring the molecular mechanism of this pathway and its functions. This review focuses on recent advances made possible by the use of STIM and Orai as molecular tools. I will describe our current understanding of the store-operated Ca 2þ entry mechanism and its emerging roles in physiology and disease, areas of uncertainty in which further progress is needed, and recent findings that are opening new directions for research in this rapidly growing field.

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“…The thereby exposed interaction domain (named either CRAC activation domain (CAD), STIM1 Orai1-activating region (SOAR) or ORAI1-activating small fragment (OASF)) directly interact with and trap Orai1 channels (8 -10), which are initially evenly distributed within the PM (11). The domains of clustered STIM1/Orai1 molecules are the sites of Ca 2ϩ influx (12)(13)(14). The minimal requirement for activation are two STIM1 molecules bound per Orai1 tetramer; however, this stoichiometry results in channels with very low open probability (P o ), whereas maximal P o is achieved with eight bound STIM1 proteins per Orai1 tetramer (15,16).…”

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confidence: 99%

Mutations of the Ca2+-sensing Stromal Interaction Molecule STIM1 Regulate Ca2+ Influx by Altered Oligomerization of STIM1 and by Destabilization of the Ca2+ Channel Orai1

Kilch

Alansary

Peglow

et al. 2013

Journal of Biological Chemistry

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Background: Calcium influx (I CRAC ) is important for proper cell function. Results: A novel STIM1 mutant increases I CRAC , Ca 2ϩ -dependently destabilizes Orai1, and alters clustering. A new mathematical model explains the phenotype. Conclusion: The molecular kinetics of STIM1 and Orai1 are major determinants of I CRAC . Significance: The diffusion trap model and alteration of Orai1 stability provide a tool for understanding I CRAC regulation.

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Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation

Cited by 235 publications

References 35 publications

Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

Store-Operated Calcium Channels: New Perspectives on Mechanism and Function

Mutations of the Ca2+-sensing Stromal Interaction Molecule STIM1 Regulate Ca2+ Influx by Altered Oligomerization of STIM1 and by Destabilization of the Ca2+ Channel Orai1

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