内质网是一个普遍的,在真核细胞中执行广泛功能的动态细胞器,包括蛋白质折叠和成熟。在压力下,ER激活适应性细胞通路,即未折叠的蛋白质反应,将信息从ER转换到细胞核,在ER环境中恢复稳态。UPR由三个膜束缚传感器组成;IRE1,PERK和ATF6。在所有的UPR传感器中,IRE1分支作为一个中央途径,协调几种途径来决定细胞命运。然而,整个过程背后的详细知识还没有被理解。以前,我们确定sMEK1是IRE1的相互作用伙伴之一。sMEK1是一种蛋白磷酸酶,这在许多关键的细胞功能如细胞凋亡中被表明,细胞增殖,和肿瘤抑制。在这项研究中,我们评估了sMEK1在IRE1信号通路中的作用。我们的数据表明sMEK1可以抑制内质网应激下的IRE1磷酸化。sMEK1的这种抑制作用可以反映在其下游效应物中,Xbp1和RIDD,在sMEK1存在下下调。我们还发现,sMEK1的阻抑作用对IRE1信号通路具有特异性,即使在长时间的内质网应激下也可以保留。我们的发现还表明,sMEK1可以在ER胁迫下抑制IRE1及其下游分子,而与其他UPR传感器无关。这些结果有助于得出机理细节,从而深入了解UPR与其他途径的不同分子连接。
The Endoplasmic Reticulum is a pervasive, dynamic cellular organelle that performs a wide range of functions in the eukaryotic cell, including protein folding and maturation. Upon stress, ER activates an adaptive cellular pathway, namely Unfolded Protein Response, that transduces information from ER to nucleus, restoring homeostasis in the ER milieu. UPR consists of three membrane-tethered sensors;
IRE1, PERK and ATF6. Among all the UPR sensors, the
IRE1 branch acts as a central pathway that orchestrates several pathways to determine cell fate. However, the detailed knowledge underlying the whole process is not understood yet. Previously, we determined the sMEK1 as one of the interacting partners of IRE1. sMEK1 is a protein phosphatase, which has been indicated in a number of critical cellular functions like apoptosis, cell proliferation, and tumour suppression. In this study, we evaluated the role of sMEK1 on the
IRE1 signalling pathway. Our data indicate that sMEK1 can inhibit
IRE1 phosphorylation under ER stress. This inhibitory effect of sMEK1 could be reflected in its downstream effectors, Xbp1 and RIDD, which are downregulated in the presence of sMEK1. We also found that the repressing effect of sMEK1 was specific to the
IRE1 signalling pathway and could be preserved even under prolonged ER stress. Our findings also indicate that sMEK1 can inhibit IRE1 and its downstream molecules under ER stress irrespective of other UPR sensors. These results help to draw the mechanistic details giving insights into different molecular connections of UPR with other pathways.