Czechowicz Paulina, Gebert Magdalena, Bartoszewska Sylwia, Kalinowski Leszek, Collawn James F, Bartoszewski Rafal
Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, F. Joliot-Curie 14a Street, Wroclaw, 50- 383, Poland.
Department of Medical Laboratory Diagnostics-Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, Gdansk, Poland.
Cell Commun Signal. 2024 Dec 2;22(1):577. doi: 10.1186/s12964-024-01967-2.
Regulation of endoplasmic reticulum (ER) homeostasis plays a critical role in maintaining cell survival. When ER stress occurs, a network of three pathways called the unfolded protein response (UPR) is activated to reestablish homeostasis. While it is known that there is cross-talk between these pathways, how this complex network is regulated is not entirely clear. Using human cancer and non-cancer cell lines, two different genome-wide approaches, and two different ER stress models, we searched for miRNAs that were decreased during the UPR and surprisingly found only one, miR-1244, that was found under all these conditions. We also verified that ER-stress related downregulation of miR-1244 expression occurred with 5 different ER stressors and was confirmed in another human cell line (HeLa S3). These analyses demonstrated that the outcome of this reduction during ER stress supported both IRE1 signaling and elevated BIP expression. Further analysis using inhibitors specific for IRE1, ATF6, and PERK also revealed that this miRNA is impacted by all three pathways of the UPR. This is the first example of a complex mechanism by which this miRNA serves as a regulatory check point for all 3 pathways that is switched off during UPR activation. In summary, the results indicate that ER stress reduction of miR-1244 expression contributes to the pro-survival arm of UPR.
内质网（ER）稳态的调节在维持细胞存活中起着关键作用。当内质网应激发生时，一个由三条途径组成的网络，即未折叠蛋白反应（UPR）被激活以重新建立稳态。虽然已知这些途径之间存在相互作用，但这个复杂网络是如何被调节的尚不完全清楚。我们使用人类癌细胞系和非癌细胞系、两种不同的全基因组方法以及两种不同的内质网应激模型，寻找在未折叠蛋白反应期间表达降低的微小RNA（miRNA），令人惊讶的是，我们只发现了一种，即miR - 1244，它在所有这些条件下均被检测到。我们还证实，miR - 1244表达的内质网应激相关下调在5种不同的内质网应激源作用下均会发生，并在另一种人类细胞系（HeLa S3）中得到证实。这些分析表明，内质网应激期间这种下调的结果支持了肌醇需求酶1（IRE1）信号传导和结合免疫球蛋白蛋白（BIP）表达的升高。使用针对IRE1、活化转录因子6（ATF6）和蛋白激酶R样内质网激酶（PERK）的特异性抑制剂进行的进一步分析还表明，这种miRNA受到未折叠蛋白反应的所有三条途径的影响。这是一个复杂机制的首个例子，通过该机制，这种miRNA作为未折叠蛋白反应激活期间关闭的所有三条途径的调节检查点。总之，结果表明内质网应激导致的miR - 1244表达降低有助于未折叠蛋白反应的促生存分支。
