Role of STIM2 in cell function and physiopathology

Abstract

An endoplasmic reticulum (ER)-resident protein that regulates cytosolic and ER free-Ca²⁺ concentration by induction of store-operated calcium entry: that is the original definition of STIM2 and its function. While its activity strongly depends on the amount of calcium stored in the ER, its function goes further, to intracellular signalling and gene expression. Initially under-studied owing to the prominent function of STIM1, STIM2 came to be regarded as vital in mice, gradually emerging as an important player in the nervous system, and cooperating with STIM1 in the immune system. STIM2 has also been proposed as a relevant player in pathological conditions related to ageing, Alzheimer's and Huntington's diseases, autoimmune disorders and cancer. The discovery of additional functions, together with new splicing forms with opposite roles, has clarified existing controversies about STIM2 function in SOCE. With STIM2 being essential for life, but apparently not for development, newly available data demonstrate a complex and still intriguing behaviour that this review summarizes, updating current knowledge of STIM2 function.

Keywords: STIM2; calcium entry; store-operated calcium entry.

Figure 1. STIM2 splicing variants

The STIM2 gene generates three different splicing variants: STIM2.2 (top panel), the first isoform described and capable of interacting with Orai and TRP channels in the PM (Williams et al. 2001); STIM2.1 (middle panel) with an insert of additional amino acids in the CAD/SOAR region (383‐VAASYLIQ‐392), which impairs STIM2.1 association with Orai and TRP channels (Miederer et al. 2015; Rana et al. 2015); STIM2.3 (bottom panel), with an alternative C‐terminal region (587‐CIHLGLGACKSE) that lacks the CaM binding and the K‐rich domains present in the other two longer isoforms (Miederer et al. 2015).

Figure 2. Function of STIM2 isoforms depending on their expression

Scheme of the four proposed models of the role of STIM2 isoforms in SOCE. Each figure depicts the STIM proteins in resting (left) and activated state (right). A, in cells where STIM1 is highly expressed, STIM2.2 homodimers mediate weak SOCE to refill the ER from either leakage or mild store depletion (Brandman et al. 2007). B, cells that express similar levels of STIM1 and STIM2.2 present heterodimers of STIM1–STIM2.2, which allow earlier responses of STIM1 triggering increased SOCE in response to mild ER depletion (Soboloff et al. 2006b; Ong et al. 2015). C, in cells that either do not express STIM1 or express a high STIM2.2:STIM1 ratio, SOCE is triggered by STIM2.2 culminating in weak or robust Ca²⁺ entry, depending on the stimuli and always smaller than those triggered by STIM1 (Liou et al. 2005; Soboloff et al. 2006b; Berna‐Erro et al. 2009). D, cells expressing low levels of the inhibitory isoform STIM2.1 do not show impaired STIM1 function presenting robust SOCE, whereas those with high levels of STIM2.1 form heterodimers of STIM1–STIM2.1 or STIM2.2–STIM 2.1 activating weak SOCE (Wang et al. 2014; Rana et al. 2015).