Differential Control of STIM1 Expression and Function by EGR Family Members in T Cells

Abstract

Antigen presentation to T cells results in their activation through T Cell Receptor (TCR) stimulation, resulting in an intricate signaling web involving multiple steps and contributors. Elevation in cytosolic Ca2+ concentration is critical for T cell activation and requires Store Operated Ca2+ entry (SOCe). A key mediator of SOCe is the type 1A transmembrane protein Stromal Interaction Molecule 1 (STIM1) that stimulates Orai-mediated Ca2+ entry upon sensing ER Ca2+ store depletion. We have recently shown that STIM1 expression is regulated by a member of the Early Growth Response (EGR) family of zinc finger transcription factors, EGR1. However, examination of T cells collected from EGR1 knockout mice revealed a paradoxical increase in basal level STIM1 expression coinciding with increased expression of EGR4, another EGR family member. We further show that control of STIM1 expression, possibly by multiple EGRs, allows for a compensatory increase of SOCe in EGR1 knockout T cells that is not observed in other cell types such as fibroblasts. This data suggests that STIM1 expression and subsequently T cell function are dynamically regulated through interplay of EGR family members. Given the critical contribution of these Ca2+ signals to both T cell expansion and cytokine production, we anticipate that these findings have significant implications on the T cell activation process itself. We further predict that our findings have important implications towards the general understanding of transcriptional control of Ca2+ signaling.