Zentrum für Molekulare Biologie der Universität Heidelberg-ZMBH, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
Traffic. 2012 Jul;13(7):992-1003. doi: 10.1111/j.1600-0854.2012.01359.x. Epub 2012 Apr 25.
STIM1 is a core component of the store-operated Ca²⁺-entry channel involved in Ca²⁺-signaling with an important role in the activation of immune cells and many other cell types. In response to cell activation, STIM1 protein senses low Ca²⁺ concentration in the lumen of the endoplasmic reticulum (ER) and activates the channel protein Orai1 in the plasma membrane by direct physical contact. The related protein STIM2 functions similar but its physiological role is less well defined. We found that STIM2, but not STIM1, contains a di-lysine ER-retention signal. This restricts the function of STIM2 as Ca²⁺ sensor to the ER while STIM1 can reach the plasma membrane. The intracellular distribution of STIM1 is regulated in a cell-cycle-dependent manner with cell surface expression of STIM1 during mitosis. Efficient retention of STIM1 in the ER during interphase depends on its lysine-rich domain and a di-arginine ER retention signal. Store-operated Ca²⁺-entry enhanced ER retention, suggesting that trafficking of STIM1 is regulated and this regulation contributes to STIM1s role as multifunctional component in Ca²⁺-signaling.
STIM1 是组成钙库操纵性钙内流通道（store-operated Ca²⁺-entry channel）的核心成分，该通道在钙信号转导中发挥重要作用，在免疫细胞和许多其他细胞类型的激活中具有重要作用。细胞激活时，STIM1 蛋白感知内质网（endoplasmic reticulum，ER）腔中的低钙浓度，并通过直接物理接触激活质膜中的通道蛋白 Orai1。相关蛋白 STIM2 的功能类似，但生理作用尚不清楚。我们发现 STIM2 而非 STIM1 含有双赖氨酸 ER 滞留信号。这将 STIM2 的 Ca²⁺传感器功能限制在 ER 中，而 STIM1 可以到达质膜。STIM1 的细胞内分布呈细胞周期依赖性调节，有丝分裂期间 STIM1 存在于质膜表面。间期 STIM1 在 ER 中的有效保留依赖于其富含赖氨酸的结构域和双精氨酸 ER 保留信号。钙库操纵性钙内流增强了 ER 保留，提示 STIM1 的运输受到调节，这种调节有助于 STIM1 作为多功能钙信号转导组分发挥作用。
