A Cytosolic STIM2 Preprotein Created by Signal Peptide Inefficiency Activates ORAI1 in a Store-independent Manner

Calcium (Ca2+) influx through the plasma membrane store-operated Ca2+ channel ORAI1 is controlled by Ca2+ sensors of the stromal interaction molecule (STIM) family. STIM1 responds to endoplasmic reticulum (ER) Ca2+ store depletion by redistributing and activating ORAI1 from regions of the ER juxtapo...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-05, Vol.286 (18), p.16174-16185
Main Authors: Graham, Sarah J.L., Dziadek, Marie A., Johnstone, Lorna S.
Format: Article
Language:English
Subjects:
Basal Ca2
Base Sequence
Calcium
Calcium - metabolism
Calcium Channels
Calcium Channels - genetics
Calcium Channels - metabolism
Cell Adhesion Molecules - genetics
Cell Adhesion Molecules - metabolism
Cytosol - metabolism
Endoplasmic Reticulum - genetics
Endoplasmic Reticulum - metabolism
HEK293 Cells
Humans
Models, Biological
Molecular Sequence Data
NF-κB Transcription Factor
NFAT Transcription Factor
ORAI1
ORAI1 Protein
Protein Precursors - genetics
Protein Precursors - metabolism
Protein Sorting Signals - physiology
Protein Translocation
Protein Transport - physiology
Signal Transduction
SOCe
STIM1
STIM2
Stromal Interaction Molecule 2
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Summary:Calcium (Ca2+) influx through the plasma membrane store-operated Ca2+ channel ORAI1 is controlled by Ca2+ sensors of the stromal interaction molecule (STIM) family. STIM1 responds to endoplasmic reticulum (ER) Ca2+ store depletion by redistributing and activating ORAI1 from regions of the ER juxtaposed to the plasma membrane. Unlike STIM1, STIM2 can regulate ORAI1 in a store-dependent and store-independent manner, but the mechanism by which this is achieved is unknown. Here we find that STIM2 is translated from a highly conserved methionine residue and is directed to the ER by an incredibly long 101-amino acid signal peptide. We find that although the majority of the total STIM2 population resides on the ER membrane, a second population escapes ER targeting to accumulate as a full-length preprotein in the cytosol, signal peptide intact. Unlike STIM2, preSTIM2 localizes to the inner leaflet of the plasma membrane where it interacts with ORAI1 to regulate basal Ca2+ concentration and Ca2+-dependent gene transcription in a store-independent manner. Furthermore, a third protein comprising a fragment of the STIM2 signal peptide is released from the ER membrane into the cytosol where it regulates gene transcription in a Ca2+-independent manner. This study establishes a new model for STIM2-mediated regulation of ORAI1 in which two distinct proteins, STIM2 and preSTIM2, control store-dependent and store-independent modes of ORAI1 activation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.206946