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J. Biol. Chem., Vol. 283, Issue 21, 14524-14531, May 23, 2008

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Novel Role for STIM1 as a Trigger for Calcium Influx Factor Production^*

From the Boston University School of Medicine, Boston, Massachusetts 02118

STIM1 has been recently identified as a Ca²⁺ sensor in endoplasmic reticulum (ER) and an initiator of the store-operated Ca²⁺ entry (SOCE) pathway, but the mechanism of SOCE activation remains controversial. Here we focus on the early ER-delimited steps of the SOCE pathway and demonstrate that STIM1 is critically involved in initiating of production of calcium influx factor (CIF), a diffusible messenger that can deliver the signal from the stores to plasma membrane and activate SOCE. We discovered that CIF production is tightly coupled with STIM1 expression and requires functional integrity of its intraluminal sterile -motif (SAM) domain. We demonstrate that 1) molecular knockdown or overexpression of STIM1 results in corresponding impairment or amplification of CIF production and 2) inherent deficiency in the ER-delimited CIF production and SOCE activation in some cell types can be a result of their deficiency in STIM1 protein; expression of a wild-type STIM1 in such cells was sufficient to fully rescue their ability to produce CIF and SOCE. We found that glycosylation sites in the ER-resident SAM domain of STIM1 are essential for initiation of CIF production. We propose that after STIM1 loses Ca²⁺ from EF hand, its intraluminal SAM domain may change conformation, and via glycosylation sites it can interact with and activate CIF-producing machinery. Thus, CIF production appears to be one of the earliest STIM1-dependent events in the ER lumen, and impairment of this process results in impaired SOCE response.

Received for publication, November 26, 2007 , and in revised form, March 11, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants RO1HL54150 and RO1HL71793 (to V. M. B.). This work was also supported by Training Grants HL007969 (to K. P.) and HL007224 (to V. Z.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3 and a supplemental movie.

¹ These authors equally contributed to this work.

² To whom correspondence should be addressed: Ion Channel and Calcium Signaling Unit, EBRC, X-704, 650 Albany St., Boston, MA 02118. Tel.: 617-638-7118; Fax: 617-638-7187; E-mail: bolotina{at}bu.edu.

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