SARAF Inactivates the Store Operated Calcium Entry Machinery to Prevent Excess Calcium Refilling

• Published in: Cell Vol. 149; no. 2; pp. 425 - 438
• Main Authors: Palty, Raz, Raveh, Adi, Kaminsky, Ido, Meller, Ruth, Reuveny, Eitan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.04.2012
• Subjects: calcium; Calcium - metabolism; Calcium Signaling; Cell Adhesion Molecules - metabolism; Cell Line; Cell Membrane - metabolism; Cytosol - metabolism; electrophysiology; endoplasmic reticulum; Flow Cytometry; heterologous gene expression; Humans; image analysis; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular Sequence Data; Neoplasm Proteins - metabolism; proteins; site-directed mutagenesis; Stromal Interaction Molecule 1; Stromal Interaction Molecule 2
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.01.055

Store operated calcium entry (SOCE) is a principal cellular process by which cells regulate basal calcium, refill intracellular Ca2+ stores, and execute a wide range of specialized activities. STIM and Orai proteins have been identified as the essential components enabling the reconstitution of Ca2+ release-activated Ca2+ (CRAC) channels that mediate SOCE. Here, we report the molecular identification of SARAF as a negative regulator of SOCE. Using heterologous expression, RNAi-mediated silencing and site directed mutagenesis combined with electrophysiological, biochemical and imaging techniques we show that SARAF is an endoplasmic reticulum membrane resident protein that associates with STIM to facilitate slow Ca2+-dependent inactivation of SOCE. SARAF plays a key role in shaping cytosolic Ca2+ signals and determining the content of the major intracellular Ca2+ stores, a role that is likely to be important in protecting cells from Ca2+ overfilling. [Display omitted] ► SARAF is a ubiquitously expressed, membrane-associated, ER resident protein ► SARAF interacts with STIM proteins ► SARAF negatively regulates store operated calcium entry into cells ► SARAF protects cells from calcium overfilling A newly identified protein, SARAF, is the long sought inhibitor of STIM and Orai1 activity that halts Ca2+-refilling when depleted ER stores have been sufficiently replenished. SARAF prevents “overfilling” of cells by calcium and the associated inappropriate responses such as excessive nuclear translocation of calcium-responsive transcription factors such as NFAT.